Randomized Phase II Trial of Hypofractionated Dose-Escalated Photon IMRT or Proton Beam Therapy Versus Conventional Photon Irradiation With Concomitant and Adjuvant Temozolomide in Patients With Newly Diagnosed Glioblastoma
PRIMARY OBJECTIVES:
I. To determine if dose-escalated and -intensified photon IMRT or proton beam therapy (using
a dose-per-fraction escalation with simultaneous integrated boost) with concomitant and
adjuvant temozolomide improves overall survival, as compared to standard-dose photon
irradiation with concomitant and adjuvant temozolomide.
SECONDARY OBJECTIVES:
I. To indirectly compare dose-escalated and -intensified photon IMRT to dose-escalated and
-intensified proton beam therapy in terms of overall survival.
II. To indirectly compare and record toxicities of dose-escalated and -intensified photon
IMRT versus dose-escalated and -intensified proton beam therapy and directly compare the
toxicities of these approaches versus standard-dose photon irradiation on the backbone of
concomitant and adjuvant temozolomide.
III. To determine if dose-escalated and -intensified photon IMRT or proton beam therapy
(using a dose-per-fraction escalation with simultaneous integrated boost) with concomitant
and adjuvant temozolomide improves perceived cognitive symptom severity, as compared to
standard-dose photon irradiation with concomitant and adjuvant temozolomide.
IV. To determine if dose-escalated and -intensified photon IMRT or proton beam therapy (using
a dose-per-fraction escalation with simultaneous integrated boost) with concomitant and
adjuvant temozolomide improves neurocognitive function, as compared to standard-dose photon
irradiation with concomitant and adjuvant temozolomide.
V. To indirectly determine if dose-escalated and -intensified proton beam therapy with
concomitant and adjuvant temozolomide improves perceived cognitive symptom severity, as
compared to dose-escalated and -intensified photon IMRT, and to directly compare symptom
burden with these approaches versus standard-dose photon irradiation on the backbone of
concomitant and adjuvant temozolomide.
VI. To indirectly determine if dose-escalated and -intensified proton beam therapy with
concomitant and adjuvant temozolomide improves neurocognitive function, as compared to
dose-escalated and -intensified photon IMRT, and to directly compare neurocognitive function
with these approaches versus standard-dose photon irradiation on the backbone of concomitant
and adjuvant temozolomide.
TERTIARY OBJECTIVES:
I. Tissue banking for future translational science projects that will be determined based on
the state of the science at the time the primary endpoint is reported and will be submitted
to National Cancer Institute (NCI) for review and approval.
II. To prospectively compare CD4 lymphopenia between dose-escalated and intensified proton
beam therapy, dose-escalated and -intensified photon IMRT, and standard-dose photon
irradiation and determine whether CD4 lymphopenia impacts overall survival.
III. To explore the most appropriate and clinically relevant technological parameters to
ensure quality and effectiveness throughout radiation therapy processes, including imaging,
simulation, patient immobilization, target and critical structure definition, treatment
planning, image guidance and delivery.
- To establish feasibility and clinical relevancy of quality assurance guidelines.
- To evaluate efficacy of quality assurance tools.
IV. To explore the most appropriate and clinically relevant advanced and standard MRI imaging
parameters.
- To evaluate the feasibility of differentiating pseudo-progression and true progression
in a multi institutional setting using MR diffusion and perfusion imaging.
- To evaluate for early, imaging biomarkers of response and overall survival.
OUTLINE: Patients are assigned to 1 of 2 groups depending on enrolling institution. Within
each group, patients will be randomized 1:2 in favor of the experimental arms.
GROUP I (PHOTON IMRT CENTERS): Patients are randomized to 1 of 2 treatment arms.
ARM A1: Patients undergo standard-dose photon irradiation using 3-dimensional conformal
radiation therapy (3D-CRT) or IMRT once daily (QD), 5 days a week for 23 fractions plus a
boost of 7 additional fractions.
ARM B: Patients undergo dose-escalated and -intensified photon IMRT QD, 5 days a week for a
total of 30 fractions.
GROUP II (PROTON CENTERS): Patients are randomized to 1 of 2 treatment arms.
ARM A2: Patients undergo standard-dose photon irradiation using 3D-CRT or IMRT as in Arm A1.
ARM C: Patients undergo dose-escalated and -intensified proton beam radiation therapy QD, 5
days a week for a total of 30 fractions.
In all treatment arms, patients receive temozolomide orally (PO) QD on days 1-49 of radiation
therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment
repeats every 28 days for up to 12 cycles in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 1 year,
every 4 months for 1 year, and then every 6 months thereafter.
Phase III Trial of Observation Versus Irradiation for a Gross Totally Resected Grade II Meningioma
PRIMARY OBJECTIVES:
I. To determine, in terms of progression-free survival (PFS), the extent of clinical benefit
of the addition of adjuvant radiotherapy (RT) to gross total resection (GTR) for patients
with newly diagnosed World Health Organization (WHO) grade II meningioma.
SECONDARY OBJECTIVES:
I. Overall survival (OS). II. Disease-specific survival (DSS). III. Toxicity (grade 3+,
exclusive of expected alopecia). IV. Neurocognitive function (NCF). V. Outcomes and patient
reported outcomes (PRO) measurements. VI. Adherence to protocol-specific target and normal
tissue parameters. VII. Concordance measurements of central versus parent-institution
pathology. VIII. Tissue microarray construction, and assessment of pHH3 mitotic index and
molecular correlates to OS.
OUTLINE: Patients are randomized to 1 of 2 arms after undergoing gross total resection.
ARM I: Patients undergo observation.
ARM II: Patients undergo radiation therapy 5 days a week over 6.5-7 weeks for a total of 33
fractions (59.4 Gy in 33 daily fractions of 1.8 Gy each).
After completion of study treatment, patients are followed up at 3, 6, and 12 months, every 6
months for year 2 and 3, then yearly for 10 years.
A Safety Run-In and Phase II Study Evaluating the Efficacy, Safety, and Impact on the Tumor Microenvironment of the Combination of Tocilizumab, Atezolizumab, and Fractionated Stereotactic Radiotherapy in Recurrent Glioblastoma
PRIMARY OBJECTIVES:
I. To determine the maximum-tolerated dose (MTD) among three sequential dose levels:
single-agent tocilizumab 4 mg/kg, single-agent tocilizumab 8 mg/kg, and tocilizumab 8 mg/kg +
atezolizumab 1680 mg (each administered with fractionated stereotactic radiation therapy
[FSRT]), to be used for subsequent phase II testing. (Safety Run-In) II. To determine the
efficacy of the combination of tocilizumab (anti-IL6R), atezolizumab (anti-PD-L1), and FSRT
in recurrent glioblastoma (GBM), as measured by the objective radiographic response rate
(ORR). (Phase II [Non-Surgical Cohort])
SECONDARY OBJECTIVES:
I. To estimate the progression-free survival (PFS) in patients with recurrent GBM treated
with the combination of tocilizumab (anti-IL6R) and FSRT (and atezolizumab [anti-PD-L1], if
dose level 3 is MTD). (Phase II Non-Surgical Cohort and Safety Run-in Cohort) II. To estimate
the overall survival (OS) in patients with recurrent GBM treated with the combination of
tocilizumab (anti-IL6R) and FSRT (and atezolizumab [anti-PD-L1], if dose level 3 is MTD)),
atezolizumab (anti-PD-L1), and FSRT. (Phase II Non-Surgical Cohort and Safety Run-in Cohort)
III. To estimate the progression-free survival (PFS) in patients with recurrent GBM treated
with the combination of tocilizumab (anti-IL6R), atezolizumab (anti-PD-L1), and FSRT. (Phase
II Surgical Cohort) IV. To estimate the overall survival (OS) in patients with recurrent GBM
treated with the combination of tocilizumab (anti-IL6R), atezolizumab (anti-PD-L1), and FSRT.
(Phase II Surgical Cohort) V. To determine the rate and severity of adverse events (AEs) of
the combination of tocilizumab (anti-IL6R), atezolizumab (anti-PD-L1), and FSRT in recurrent
glioblastoma according to Common Terminology Criteria for Adverse Events (CTCAE) version (v)
5.0. (Separately in the Nonsurgical and Surgical Cohorts)
EXPLORATORY OBJECTIVES:
I. To determine the effect of the combination of atezolizumab (anti-PD-L1) and FSRT, with
versus (vs.) without tocilizumab (anti-IL6R), on the GBM immune microenvironment. (Phase II
Surgical Cohort) II. To evaluate the pharmacodynamic impact of the combination of tocilizumab
(anti-IL6R), atezolizumab (anti-PD-L1), and FSRT on peripheral blood immune cell populations.
(Phase II Surgical Cohort) III. To detect tumor and/or blood biomarkers associated with the
outcomes of OS, PFS, and/or ORR in patients with recurrent GBM treated with the combination
of tocilizumab (anti-IL6R), atezolizumab (anti-PD-L1), and FSRT. (Phase II Non-Surgical
Cohort)
OUTLINE:
SAFETY RUN-IN: Patients receive systemic treatment with either tocilizumab intravenously (IV)
over 60 minutes with or without atezolizumab IV over 30-60 minutes on day 1. Within 3-7 days,
patients undergo FSRT for 3 fractions over 3-5 days. Starting 4 weeks from the first dose of
systemic treatment, patients resume treatment with tocilizumab with or without atezolizumab.
Treatment repeats every 4 weeks for up to 2 years in the absence of disease progression or
unacceptable toxicity. Patients undergo magnetic resonance imaging (MRI) throughout the
trial. (CLOSED TO ACCRUAL 08-AUG-2023)
GROUP I (NON-SURGICAL COHORT): Patients receive systemic treatment with tocilizumab IV over
60 minutes with or without atezolizumab IV over 30-60 minutes on day 1. Within 3-7 days,
patients undergo FSRT for 3 fractions over 3-5 days in the absence of disease progression or
unacceptable toxicity. Starting 4 weeks from the first dose of systemic treatment, patients
resume treatment with tocilizumab with or without atezolizumab. Treatment repeats every 4
weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.
Patients undergo MRI throughout the trial.
GROUP II (SURGICAL COHORT): Patients are randomized to 1 of 2 arms.
ARM I: Patients receive systemic treatment with tocilizumab IV over 60 minutes with or
without atezolizumab IV over 30-60 minutes on day 1. Within 3-7 days, patients undergo FSRT
for 3 fractions over 3-5 days. Within 7-14 days after FSRT, patients undergo surgery. Within
21-24 days from the first dose of systemic treatment, patients resume treatment with
tocilizumab with or without atezolizumab. Treatment repeats every 4 weeks for up to 2 years
in the absence of disease progression or unacceptable toxicity. Patients undergo MRI
throughout the trial, as well as blood sample and tumor tissue collection on study.
ARM II: Patients receive systemic treatment with atezolizumab IV over 30-60 minutes on day 1.
Within 3-7 days, patients undergo FSRT for 3-5 fractions over 3-5 days. Within 7-14 days
after FSRT, patients undergo surgery. Within 21-24 days from the first dose of systemic
treatment, patients resume treatment with tocilizumab IV over 60 minutes with or without
atezolizumab. Treatment repeats every 4 weeks for up to 2 years in the absence of disease
progression or unacceptable toxicity. Patients undergo MRI throughout the trial, as well as
blood sample and tumor tissue collection on study.
After completion of study treatment, patients are followed up at 30 days, 3, 6, 9, 12, 18,
and 24 months.
A Phase III Randomized Trial of Radiotherapy Optimization for Low-Risk HER2-Positive Breast Cancer (HERO)
The landmark trials that established breast conservation therapy (BCT) (breast-conserving
surgery followed by adjuvant breast irradiation) as a suitable alternative to mastectomy were
conducted in an era that predated biological subtyping of breast cancer and the use of
HER2-directed therapies in patients with HER2+ cancers. These trials established adjuvant
radiotherapy following breast-conserving surgery as necessary to maximize local control, yet,
in the intervening years, overall outcomes have improved significantly owing to widespread
adoption of screening mammography, resulting in a substantial reduction in average tumor size
at diagnosis, as well as improvements in surgical techniques and, crucial for this proposal,
the development of highly active systemic therapies.
Before the development of HER2-targeted therapies, patients with HER2-driven localized breast
cancer had among the highest rates of local recurrence. However, with improved identification
of these patients and the advent of HER2-directed therapies, outcomes have improved
significantly, and trials have sought to optimize treatment to reduce the morbidity of both
local and systemic treatment. Among the most salient of these examples is the APT trial, a
single-arm adjuvant study that enrolled 410 breast cancer patients with HER2+ tumors ≤ 3cm in
size and negative axillary nodes, who received adjuvant systemic therapy with weekly
paclitaxel and trastuzumab for 12 weeks (TH) followed by 9 months of trastuzumab monotherapy.
In addition to demonstrating a very low incidence of distant recurrence, among those on the
trial who underwent BCT (lumpectomy and radiation, n = 244), only 2 local recurrence (LR)
events have been reported after 7 years of follow-up (7-year LR = 1.2%), representing among
the most favorable local outcomes of any breast cancer cohort studied to date. Confirmatory
results are forthcoming from the ATEMPT trial, which evaluated the antibody-drug conjugate
T-DM1 (ado-trastuzumab emtansine) (n=383) vs the TH regimen from the APT trial (n = 114),
thus far showing only 3 LRs in each arm with a median 3-years of follow-up. Importantly, per
the current standard of care for HER2+ patients undergoing BCT, all patients presumably
received adjuvant breast radiotherapy.
The balance of the BCT literature, including a landmark meta-analysis by the Early Breast
Cancer Trialists' Collaborative Group, suggests that adjuvant radiotherapy approximately
halves the risk of local recurrence following lumpectomy across all analyzable subgroups.
While the relative benefit appears constant across subgroups, the absolute benefit of
adjuvant radiotherapy varies with the underlying risk. Taking the favorable results of the
APT trial (1.2% 7-year LR), if one presumes that omission of radiotherapy yields a doubling
or tripling of local recurrence (based on the observed RR of 0.5 - 0.66 for those receiving
radiotherapy across the preponderance of historical trials), this population might have
manifested a LR rate of 2.4 - 3.6% with the omission of radiotherapy. That is to say, the
hypothesis is that administration of RT to APT patients undergoing BCT may have reduced the
7-year absolute risk of LR by only 1.2-2.4%. Through the identification of patients who are
at low risk of LR, it may be acceptable for such patients to forego radiation. This
hypothesis will be studied by evaluating omission of radiotherapy among patients with pT1N0
disease at breast-conserving surgery who receive adjuvant HER2-directed therapy
(trastuzumab/paclitaxel preferred, other options per protocol), or with clinical tumors ≤ 3
cm and clinically negative axillary nodes (cN0) who achieve a pathologic complete response
(pCR; ypT0N0) following preoperative (neoadjuvant) administration of HER2-directed therapy
(trastuzumab/paclitaxel preferred, other options per protocol). It is expcted that the 5-year
LR rate for this population omitting radiotherapy will be 2% or less, and that omission of
radiation will not have a measurable impact on regional and distant recurrences or overall
survival.
The practice of breast radiation oncology has benefited immensely from practice-changing
trials that have refined the application of adjuvant radiotherapy since the early surgical
studies determined whole breast radiotherapy to be necessary following lumpectomy. There are
now several favorable breast cancer subtypes in which patients routinely forego radiotherapy
after trials demonstrating modest benefits in terms of local recurrence and no impact on
distant recurrence or survival, such as among small, low grade luminal cancers in older women
and "good-risk" DCIS. Therefore, this will study the omission of radiotherapy among a
population of HER2+ breast cancer patients who are now appreciated to also have favorable
risk, so as to similarly weigh the attendant inconveniences, cost and morbidity of
radiotherapy in light of an established absolute benefit, which may prove to be modest.
Phase III Trial of Stereotactic Radiosurgery (SRS) Versus Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) for 10 or Fewer Brain Metastases From Small Cell Lung Cancer
PRIMARY OBJECTIVE:
I. Determine whether stereotactic radiosurgery (SRS) relative to whole brain radiotherapy
with hippocampal avoidance (HA-WBRT) plus memantine hydrochloride (memantine) for brain
metastases from small cell lung cancer (SCLC) prevents cognitive function failure as measured
by cognitive decline on a battery of tests: the Hopkins Verbal Learning Test - Revised
(HVLT-R), Controlled Oral Word Association (COWA) test, and the Trail Making Test (TMT).
SECONDARY OBJECTIVES:
I. Determine whether SRS relative to HA-WBRT plus memantine for brain metastases from SCLC
preserves cognitive function as separately measured by the HVLT-R, COWA, TMT Parts A and B,
and Clinical Trial Battery Composite (CTB COMP).
II. Assess perceived difficulties in cognitive abilities using Patient Reported Outcomes
Measurement Information System (PROMIS) after SRS relative to HA-WBRT plus memantine for
brain metastases from SCLC.
III. Assess symptom burden using the MD Anderson Symptom Inventory for brain tumor (MDASI-BT)
after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC.
IV. Compare cumulative incidence of intracranial disease progression after SRS relative to
HA-WBRT plus memantine for brain metastases from SCLC.
V. Compare overall survival after SRS relative to HA-WBRT plus memantine for brain metastases
from SCLC.
VI. Compare cumulative incidence of neurologic death after SRS relative to HA-WBRT plus
memantine for brain metastases from SCLC.
VII. Compare the number of salvage procedures used to manage recurrent intracranial disease
following SRS relative to HA-WBRT plus memantine for SCLC brain metastases.
VIII. Compare adverse events between the treatment arms according to the National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0
criteria.
IX. Compare the risk of developing cerebral necrosis between SRS and HA-WBRT plus memantine
in patients receiving concurrent immunotherapy.
EXPLORATORY OBJECTIVES:
I. Compare cumulative incidence of local brain recurrence, distant brain relapse, and
leptomeningeal dissemination after SRS relative to HA-WBRT plus memantine for brain
metastases from SCLC.
II. Compare the cost of brain-related therapies and quality-adjusted life years in patients
who receive SRS relative to HA-WBRT plus memantine for brain metastases from SCLC.
III. Evaluate the time delay to salvage WBRT or HA-WBRT in patients enrolled on the SRS arm.
IV. Evaluate whether a time delay for chemotherapy in patients receiving HA-WBRT plus
memantine relative to SRS for brain metastases from SCLC has an effect on overall survival.
V. Evaluate baseline magnetic resonance (MR) imaging biomarkers of white matter injury and
hippocampal volumetry as potential predictors of cognitive decline and differential benefit
from SRS relative to HA-WBRT plus memantine for brain metastases from SCLC.
VI. Evaluate the correlation between neurocognitive functioning and patient-reported
outcomes.
VII. Collect serum, plasma and imaging studies for future translational research analyses.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients undergo SRS over 1 day (in some cases several days).
ARM II: Patients undergo HA-WBRT once daily (QD) for 2 weeks in the absence of disease
progression or unacceptable toxicity. Patients also receive memantine orally (PO) QD or twice
daily (BID) for up to 24 weeks in the absence of disease progression or unacceptable
toxicity.
After completion of study treatment, patients are followed up every 2-3 months for 1 year,
and then every 6 months thereafter.
Parallel Phase III Randomized Trials for High Risk Prostate Cancer Evaluating De-Intensification for Lower Genomic Risk and Intensification of Concurrent Therapy for Higher Genomic Risk With Radiation (PREDICT-RT*)
PRIMARY OBJECTIVES:
I. To determine whether men with National Comprehensive Cancer Network (NCCN) high risk
prostate cancer who are in the lower 2/3 of Decipher genomic risk (=< 0.85) can be treated
with 12 months androgen deprivation therapy (ADT) plus radiation therapy (RT) instead of 24
months ADT+RT and experience non-inferior metastasis-free survival. (De-intensification
study) II. To determine whether men with NCCN high risk prostate cancer who are in the upper
1/3 of Decipher genomic risk (> 0.85) or have node-positive disease by conventional imaging
(magnetic resonance imaging [MRI] or computed tomography [CT] scan) will have a superior
metastasis-free survival (MFS) through treatment intensification with apalutamide added to
the standard of RT plus 24 month ADT. (Intensification study)
SECONDARY OBJECTIVES:
I. To compare overall survival (OS) between the standard of care (RT plus 24 months of ADT)
and either the de-intensification (RT plus 12 months of ADT) or intensification arm (RT plus
24 months of ADT plus apalutamide). (De-intensification and intensification studies) II. To
compare time to prostate specific antigen (PSA) failure or start of salvage treatment between
the standard of care (RT plus 24 months of ADT) and either the de-intensification arm (RT
plus 12 months of ADT) or intensification arm (RT plus 24 months of ADT plus apalutamide).
(De-intensification and intensification studies) III. To compare PSA failure-free survival
with non-castrate testosterone and no additional therapies between the standard of care (RT
plus 24 months of ADT) and either the de-intensification arm (RT plus 12 months of ADT) or
intensification arm (RT plus 24 months of ADT plus apalutamide). (De-intensification and
intensification studies) IV. To compare MFS judged based on either standard or molecular
imaging between the standard of care (RT plus 24 months of ADT) and either the
de-intensification arm (RT plus 12 months of ADT) or intensification arm (RT plus 24 months
of ADT plus apalutamide). (De-intensification and intensification studies) V. To compare
prostate cancer-specific mortality between the standard of care (RT plus 24 months of ADT)
and either the de-intensification arm (RT plus 12 months of ADT) or intensification arm (RT
plus 24 months of ADT plus apalutamide). (De-intensification and intensification studies) VI.
To compare testosterone levels at the time of PSA failure and metastases between the standard
of care (RT plus 24 months of ADT) and either the de-intensification arm (RT plus 12 months
of ADT) or intensification arm (RT plus 24 months of ADT plus apalutamide).
(De-intensification and intensification studies) VII. To compare time to testosterone
recovery (defined as a T > 200) between the standard of care (RT plus 24 months of ADT) and
either the de-intensification arm (RT plus 12 months of ADT) or intensification arm (RT plus
24 months of ADT plus apalutamide). (De-intensification and intensification studies) VIII. To
compare adverse events, both clinician-reported using Common Terminology Criteria for Adverse
Events (CTCAE) version (v) 5.0 and patient-reported using Patient Reported Outcome
(PRO)-CTCAE items, between the standard of care (RT plus 24 months of ADT) and either the
de-intensification arm (RT plus 12 months of ADT) or intensification arm (RT plus 24 months
of ADT plus apalutamide). (De-intensification and intensification studies)
EXPLORATORY OBJECTIVES:
I. To compare changes in cardio-metabolic markers, including body mass index, and waist
circumference, between the standard of care (RT plus 24 months of ADT) and either the
de-intensification arm (RT plus 12 months of ADT) or intensification arm (RT plus 24 months
of ADT plus apalutamide). (De-intensification and intensification studies) II. To determine a
machine learning/artificial intelligence algorithm for radiotherapy quality assurance.
(De-intensification and Intensification studies) III. To perform future translational
correlative studies using biological and imaging data. (De-intensification and
intensification studies) IV. Impact of PET use in high-risk prostate cancer
PATIENT-REPORTED OUTCOMES OBJECTIVES:
PRIMARY OBJECTIVES:
I. To compare sexual and hormonal function related quality of life, as measured by the
Expanded Prostate Cancer Index Composite-26 (EPIC), between the standard of care (RT plus 24
months of ADT) and the de-intensification arm (RT plus 12 months of ADT). (De-Intensification
Study) II. To compare fatigue, as measured by the Patient Reported Outcomes Measurement
Information System (PROMIS)-Fatigue instrument, between the standard of care (RT plus 24
months of ADT) and the intensification arm (RT plus 24 months of ADT plus apalutamide).
(Intensification Study)
SECONDARY OBJECTIVES:
I. To compare depression, as measured by the PROMIS-depression, between the standard of care
(RT plus 24 months of ADT) and the de-intensification arm (RT plus 12 months of ADT).
(De-Intensification Study) II. To compare depression, as measured by the PROMIS-depression,
between the standard of care (RT plus 24 months of ADT) and the intensification arm (RT plus
24 months of ADT plus apalutamide). (Intensification Study)
EXPLORATORY OBJECTIVES:
I. To compare cognition, as measured by the Functional Assessment of Chronic Illness
Therapy-Cognitive (FACT-Cog) perceived cognitive abilities subscale, between the standard of
care (RT plus 24 months of ADT) and the de-intensification arm (RT plus 12 months of ADT).
(De-Intensification Study) II. To compare bowel and urinary function related quality of life,
as measured by the Expanded Prostate Cancer Index Composite-26 (EPIC), between the standard
of care (RT plus 24 months of ADT) and the de-intensification arm (RT plus 12 months of ADT).
(De-Intensification Study) III. To compare fatigue, as measured by the PROMIS-Fatigue
instrument, between the standard of care (RT plus 24 months of ADT) and the
de-intensification arm (RT plus 12 months of ADT). (De-Intensification Study) IV. To compare
sexual and hormonal function related quality of life, as measured by the Expanded Prostate
Cancer Index Composite-26 (EPIC), between the standard of care (RT plus 24 months of ADT) and
the intensification arm (RT plus 24 months of ADT plus apalutamide). (Intensification Study)
V. To compare bowel and urinary function related quality of life, as measured by the Expanded
Prostate Cancer Index Composite-26 (EPIC), between the standard of care (RT plus 24 months of
ADT) and the intensification arm (RT plus 24 months of ADT plus apalutamide).
(Intensification Study) VI. To compare cognition, as measured by the Functional Assessment of
Chronic Illness Therapy-Cognitive (FACT-Cog) perceived cognitive abilities subscale, between
the standard of care (RT plus 24 months of ADT) and the intensification arm (RT plus 24
months of ADT plus apalutamide). (Intensification Study)
OUTLINE: Patients are randomized to 1 of 4 arms.
DE-INTENSIFICATION STUDY (DECIPHER SCORE =< 0.85):
ARM I: Patients undergo radiation therapy (RT) over 2-11 weeks and receive ADT (consisting of
either leuprolide, goserelin, triptorelin, degarelix, buserelin or histrelin and bicalutamide
or flutamide) for 24 months in the absence of disease progression or unacceptable toxicity.
ARM II: Patients undergo RT over 2-11 weeks and receive ADT (consisting of either leuprolide,
goserelin, triptorelin, degarelix, buserelin or histrelin and bicalutamide or flutamide) for
12 months in the absence of disease progression or unacceptable toxicity.
INTENSIFICATION STUDY (DECIPHER SCORE > 0.85 OR NODE POSITIVE):
ARM III: Patients undergo RT over 2-11 weeks and receive ADT (consisting of either
leuprolide, goserelin, triptorelin, degarelix, buserelin or histrelin and bicalutamide or
flutamide) for 24 months in the absence of disease progression or unacceptable toxicity.
ARM IV: Patients undergo RT over 2-11 weeks and receive ADT (consisting of either leuprolide,
goserelin, triptorelin, degarelix, buserelin or histrelin) for 24 months in the absence of
disease progression or unacceptable toxicity. Patients also receive apalutamide orally (PO)
once daily (QD). Treatment repeats every 90 days for up to 8 cycles (24 months) in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up annually.
Parallel Phase III Randomized Trials of Genomic-Risk Stratified Unfavorable Intermediate Risk Prostate Cancer: De-Intensification and Intensification Clinical Trial Evaluation (GUIDANCE)
PRIMARY OBJECTIVES:
I. To determine whether men with National Comprehensive Cancer Network (NCCN) unfavorable
intermediate risk (UIR) prostate cancer and lower Decipher genomic risk (Decipher score <
0.40) treated with radiation therapy (RT) alone instead of 6 months androgen deprivation
therapy (ADT) + RT experience non-inferior rate of distant metastasis. (De-intensification
study) II. To determine whether men with NCCN UIR prostate cancer who are in the higher
genomic risk (Decipher score >= 0.40) will have a superior metastasis-free survival through
treatment intensification with darolutamide added to the standard of RT plus 6 months ADT.
(Intensification study)
SECONDARY OBJECTIVES:
I. To compare overall survival (OS) between the standard of care (RT plus 6 months of ADT)
and either the de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus
darolutamide) interventions.
II. To compare time to prostate specific antigen (PSA) failure between the standard of care
(RT plus 6 months of ADT) and either the de-intensification (RT alone) or intensification (RT
plus 6 months of ADT plus darolutamide) interventions.
III. To compare metastasis free survival (MFS) based on conventional imaging between the
standard of care (RT plus 6 months of ADT) and de-intensification intervention (RT alone).
IV. To compare MFS based on either conventional and/or molecular imaging between the standard
of care (RT plus 6 months of ADT) and either the de-intensification (RT alone) or
intensification (RT plus 6 months of ADT plus darolutamide) interventions.
V. To compare cumulative incidence of locoregional failure based upon conventional imaging
and/ or biopsy between standard of care (RT plus 6 months of ADT) and either the
de-intensification (RT alone) or intensification (RT plus 6 months ADT plus darolutamide)
interventions.
VI. To compare cumulative incidence of distant metastasis based upon conventional imaging
between standard of care (RT plus 6 months of ADT) and intensification intervention (RT plus
6 months ADT plus darolutamide).
VII. To compare cumulative incidence of distant metastasis based upon either conventional
and/or molecular imaging between standard of care (RT plus 6 months of ADT) and either the
de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus darolutamide)
interventions.
VIII. To compare prostate cancer-specific mortality between the standard of care (RT plus 6
months of ADT) and either the de-intensification (RT alone) or intensification (RT plus 6
months of ADT plus darolutamide) interventions.
IX. To compare sexual and hormonal related quality of life, as measured by the Expanded
Prostate Cancer Index Composite-26 (EPIC), between the standard of care (RT plus 6 months of
ADT) and either the de-intensification (RT alone) or intensification (RT plus 6 months of ADT
plus darolutamide) interventions.
X. To compare fatigue, as measured by the Patient Reported Outcomes Measurement Information
System (PROMIS)-Fatigue instrument, between the standard of care (RT plus 6 months of ADT)
and either the de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus
darolutamide) interventions.
XI. To compare cognition, as measured by the Functional Assessment of Chronic Illness
Therapy-Cognitive (FACT-Cog) perceived cognitive abilities subscale, between the standard of
care (RT plus 6 months of ADT) and either the de-intensification (RT alone) or
intensification (RT plus 6 months of ADT plus darolutamide) interventions.
EXPLORATORY OBJECTIVES:
I. To compare changes in cardio-metabolic markers, including body mass index, lipids, blood
glucose, complete blood count (CBC), comprehensive metabolic panel (CMP), and hemoglobin
(Hgb) A1c, between the standard of care (RT plus 6 months of ADT) and either the
de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus darolutamide)
interventions.
II. To compare PSA failure-free survival with non-castrate testosterone and no additional
therapies between the standard of care (RT plus 6 months of ADT) and either the
de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus darolutamide)
interventions.
III. To compare cumulative incidence of locoregional failure based upon either conventional
and/or molecular imaging between standard of care (RT plus 6 months of ADT) and either the
de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus darolutamide)
interventions.
IV. To compare castrate-resistant prostate cancer (CRPC) between the standard of care (RT
plus 6 months of ADT) and either the de-intensification (RT alone) or intensification (RT
plus 6 months of ADT plus darolutamide) interventions.
V. To compare bowel and urinary function related quality of life, as measured by the Expanded
Prostate Cancer Index Composite-26 (EPIC), between the standard of care (RT plus 6 months of
ADT) and either the de-intensification (RT alone) or intensification (RT plus 6 months of ADT
plus darolutamide) interventions.
VI. To compare time to testosterone recovery (defined as a T > 200ng/dL) between the standard
of care (RT plus 6 months of ADT) and intensification (RT plus 6 months of ADT plus
darolutamide) interventions.
VII. To compare health utilities, as measured by the European Quality of Life Five Dimension
Five Level Scale (EQ-5D-5L), between the standard of care (RT plus 6 months of ADT) and
either the de-intensification (RT alone) or intensification (RT plus 6 months of ADT plus
darolutamide) interventions.
VIII. To develop and assess a machine learning/artificial intelligence algorithm for
radiotherapy planning and/or quality assurance.
IX. To perform future translational correlative studies using biological data, Decipher
results, and clinical outcomes.
OUTLINE:
DE-INTENSIFICATION STUDY: Patients with Decipher score < 0.40 are randomized to 1 of 2 arms.
ARM I: Patients undergo RT using a recognized regimen (2-3 days a week or 5 days a week for
2-11 weeks) in the absence of disease progression or unacceptable toxicity.
ARM II: Patients undergo RT as Arm I. Patients also receive ADT consisting of leuprolide,
goserelin, buserelin, histrelin, triptorelin, degarelix, or relugolix at the discretion of
the treating physician, for 6 months in the absence of disease progression or unacceptable
toxicity. Patients may also receive bicalutamide or flutamide for 0, 30 or 180 days.
INTENSIFICATION STUDY: Patients with Decipher score >= 0.40 are randomized to 1 of 2 arms.
ARM III: Patients receive treatment as in Arm II.
ARM IV: Patients receive RT and ADT as in Arm II. Patients also receive darolutamide orally
(PO) twice daily (BID). Treatment repeats every 90 days for up to 2 cycles in the absence of
disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 3, 6, 12, 24, 36, 48 and 60
months.
A Phase II Double-Blinded, Placebo-Controlled Trial of PROstate OligoMETastatic RadiotHErapy With or Without ANdrogen Deprivation Therapy in Oligometastatic Prostate Cancer (NRG Promethean)
PRIMARY OBJECTIVE:
I. Compare conventional radiological progression-free survival (rPFS) for positron emission
tomography (PET)-detected, biochemically recurrent, oligometastatic, castration-sensitive
prostate cancer patients treated with stereotactic ablative body radiation therapy (SABR)
plus placebo versus (vs.) SABR plus relugolix.
SECONDARY OBJECTIVES:
I. Compare conventional or PET-based radiological progression-free survival (prPFS) between
treatment arms.
II. Compare patient-reported sexual and hormonal quality of life as assessed by corresponding
Expanded Prostate Cancer Index Composite Short Form (EPIC-26) domains between treatment arms.
III. Compare other measures of quality of life obtained from the European Quality of Life
Five Dimension Five Level Scale Questionnaire (EQ5D-5L), European Organization for Research
and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-30), and Patient
Reported Outcomes Measurement Information System (PROMIS) Fatigue instruments between the two
treatment arms.
IV. Compare time to salvage therapy and time to castration-resistance between treatment arms.
V. Compare local progression (SABR-targeted lesion), biochemical progression, distant
metastases, prostate cancer-specific mortality, metastasis-free survival, and overall
survival between treatment arms.
VI. Determine adverse events rates and compare rates between the two treatment arms.
EXPLORATORY OBJECTIVE:
I. Evaluate genomic and peripheral tissue and blood markers of treatment response.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive placebo orally (PO) once daily (QD) on days 1-180 (three tablets on
Day 1, one tablet daily on Days 2-180) and undergo SABR for 1-3 weeks in the absence of
disease progression or unacceptable toxicity.
ARM II: Patients receive relugolix PO QD on days 1-180 (three tablets on Day 1, one tablet
daily on Days 2-180) and undergo SABR for 1-3 weeks in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, patients are followed up at 3 and 6 months, every 6
months for 4 years, and then annually thereafter.
Limited Stage Small Cell Lung Cancer (LS-SCLC): A Phase III Randomized Study of Chemoradiation Versus Chemoradiation Plus Atezolizumab
PRIMARY OBJECTIVE:
I. To compare overall survival (OS) for patients with LS-SCLC treated with chemoradiation +/-
atezolizumab.
SECONDARY OBJECTIVES:
I. To compare progression free survival (PFS) for patients with limited stage small cell lung
cancer (LS-SCLC) treated with chemoradiation +/- atezolizumab.
II. To determine overall response rate (ORR), rates of local control, and distant metastases
free survival with chemoradiation +/- atezolizumab.
III. To characterize immune mediated and non-immune mediated toxicity from chemoradiotherapy
plus atezolizumab.
IV. To compare quality of life, as measured by the Functional Assessment of Cancer
Therapy-Trial Outcome Index (FACT-TOI), for patients undergoing chemoradiation +/-
atezolizumab.
V. To evaluate the quality-adjusted survival, using scores from the 5-level EuroQol
5-dimensional questionnaire (EQ-5D-5L), of chemoradiation +/- atezolizumab for patients with
LS-SCLC.
VI. To characterize fatigue, as measured by the Patient-Reported Outcomes Measurement
Information System (PROMIS), following chemoradiation +/- atezolizumab.
VII. To determine the association of blood based tumor mutational burden (bTMB) and
tissue-based tumor mutational burden (tTMB) with clinical outcome.
EXPLORATORY OBJECTIVES:
I. To collect biospecimens at baseline, day 1 and 3 months after the end of
chemoradiotherapy, to allow for future analyses.
II. To characterize patient-reported symptomatic toxicities measured by the Patient-Reported
Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE).
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive etoposide intravenously (IV) on days 1-3 and cisplatin IV or
carboplatin IV on day 1. Cycles repeat every 21 days for 3 cycles in the absence of disease
progression or unacceptable toxicity. Patients also undergo three-dimensional conformal
radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) twice daily (BID)
for approximately 3 weeks or once daily (QD) for approximately 6-7 weeks in the absence of
disease progression or unacceptable toxicity. Patients undergo blood specimen collection
throughout the trial.
ARM II: Patients receive treatment as in Arm I. Patients also receive atezolizumab IV over
30-60 minutes on day 1 or 2 of each chemotherapy cycle. Cycles repeat every 3 weeks for 17
cycles (1 year) in the absence of disease progression or unacceptable toxicity. Patients
undergo blood specimen collection throughout the trial.
After completion of study treatment, patients are followed up every 3 months for 2 years,
then every 6 months for 3 years, then annually thereafter.
Androgen Deprivation Therapy and High Dose Radiotherapy With or Without Whole-Pelvic Radiotherapy in Unfavorable Intermediate or Favorable High Risk Prostate Cancer: A Phase III Randomized Trial
OBJECTIVES:
Primary
- Demonstrate that prophylactic, neoadjuvant, androgen-deprivation therapy (NADT) and
whole-pelvic radiation therapy (WPRT) will result in improvement in overall survival
(OS) of patients with "unfavorable" intermediate-risk or "favorable" high-risk prostate
cancer compared to NADT and high-dose prostate (P) and seminal vesicle (SV) radiation
therapy (RT) using intensity-modulated RT (IMRT) or external-beam RT (EBRT) with a
high-dose rate (HDR) or a permanent prostate (radioactive seed) implant (PPI) boost.
Secondary
- Demonstrate that prophylactic WPRT improves biochemical control.
- Determine the distant metastasis (DM)-free survival.
- Determine the cause-specific survival (CSS).
- Compare acute and late treatment-adverse events between patients receiving NADT and WPRT
versus NADT, P, and SV RT.
- Determine whether health-related quality of life (HRQOL), as measured by the Expanded
Prostate Cancer Index Composite (EPIC), significantly worsens with increasing
aggressiveness of treatment (i.e., Arm 2, NADT + WPRT).
- Determine whether more aggressive treatment (Arm 2, NADT + WPRT) is associated with a
greater increase in fatigue (PROMIS Fatigue Short Form) from baseline to last week of
treatment, and a greater increase in circulating inflammatory markers (IL-1, IL-1ra,
IL-6, tumor necrosis factor (TNF)-alpha, and C-reactive protein).
- Demonstrate an incremental gain in OS and CSS with more aggressive therapy that
outweighs any detriments in the primary generic domains of HRQOL (i.e., mobility,
self-care, usual activities, pain/discomfort, and anxiety/depression).
- Determine whether changes in fatigue from baseline to the next three time points (week
prior to RT, last week of treatment, and 3 months after treatment) are associated with
changes in circulating cytokines, mood, sleep, and daily activities across the same time
points.
- Collect paraffin-embedded tissue blocks, plasma, whole blood, and urine for planned and
future translational research analyses.
OUTLINE: This is a multicenter study. Patients are stratified according to moderate- to
high-risk groups as listed in the Disease Characteristics of this abstract, type of
radiotherapy boost (IMRT vs brachytherapy [Low-dose rate (LDR) using PPI or HDR]), and
duration of androgen-deprivation therapy (short-term [6 months] vs long-term [32 months]).
Patients are randomized to 1 of 2 treatment arms.
All patients receive neoadjuvant androgen-deprivation therapy comprising bicalutamide orally
(PO) once daily or flutamide PO thrice daily for 6 months, and luteinizing hormone-releasing
hormone (LHRH) agonist/antagonist therapy comprising leuprolide acetate, goserelin acetate,
buserelin, triptorelin, or degarelix subcutaneously (SC) or intramuscularly (IM) every 1 to 3
months beginning 2 months prior to radiotherapy and continuing for 6 or 32 months.
Radiotherapy begins within 8 weeks after beginning LHRH agonist/antagonist injection.
- Arm I: Patients undergo high-dose radiotherapy of the prostate and seminal vesicles
using intensity-modulated radiotherapy (IMRT)* or 3D-conformal radiation therapy
(3D-CRT)* once daily, 5 days a week, for approximately 9 weeks. Patients may also
undergo permanent prostate implant (PPI) brachytherapy or high-dose rate brachytherapy
(iodine I 125 or palladium Pd 103 may be used as the radioisotope).
- Arm II: Patients undergo whole-pelvic radiotherapy (WPRT)* (3D-CRT or IMRT) once daily,
5 days a week, for approximately 9 weeks. Patients may also undergo brachytherapy as in
arm I.
NOTE: * Patients undergoing brachytherapy implant receive 5 weeks of IMRT, 3D-CRT, or WPRT.
Patients may undergo blood and urine sample collection for correlative studies. Primary tumor
tissue samples may also be collected.
Patients may complete the Expanded Prostate Cancer Index Composite (EPIC), the PROMIS-Fatigue
Short Form, and the EuroQol (EQ-5D) quality-of-life (QOL) questionnaires at baseline and
periodically during treatment. Patients who participate in the QOL portion of the study must
also agree to periodic blood collection.
After completion of study therapy, patients are followed up every 3 months for 1 year, every
6 months for 3 years, and then yearly thereafter.
Colon Adjuvant Chemotherapy Based on Evaluation of Residual Disease
Currently, there are no biomarkers validated prospectively in randomized studies for resected
colon cancer to determine need for adjuvant chemotherapy. However, circulating tumor DNA
(ctDNA) shed into the bloodstream represents a highly specific and sensitive approach
(especially with serial monitoring) for identifying microscopic or residual tumor cells in
colon cancer patients and may outperform traditional clinical and pathological features in
prognosticating risk for recurrence. Colon cancer patients who do not have detectable ctDNA
(ctDNA-) are at a much lower risk of recurrence and may not need adjuvant chemotherapy.
Furthermore, for colon cancer pts with detectable ctDNA (ctDNA+) who are at a very high risk
of recurrence, the optimal adjuvant chemotherapy regimen has not been established. We
hypothesize that for pts whose colon cancer has been resected, ctDNA status may be used to
risk stratify for making decisions about adjuvant chemotherapy.
A Phase III Clinical Trial Evaluating De-Escalation of Breast Radiation for Conservative Treatment of Stage I, Hormone Sensitive, HER-2 Negative, Oncotype Recurrence Score Less Than or Equal to 18 Breast Cancer
Breast conservation therapy for early stage breast cancer has been an important achievement
of oncology practice in the last half century and breast radiotherapy (RT) has been essential
in its development. Several seminal randomized clinical trials conducted in the 1980's era
demonstrated that breast radiotherapy following lumpectomy yielded overall survival outcomes
equivalent to mastectomy for treatment of early stage invasive breast cancer leading to the
National Institute of Health (NIH) Consensus Conference statement in 1991 supporting breast
conservation treatment.This established lumpectomy with RT as an alternative to mastectomy
and subsequently the rate of breast conservation for eligible breast cancer patients rose
steadily. Shortly thereafter, investigators recognized that the toxicity, patient burden, and
geographic barriers associated with the protracted treatment course for breast RT was a
potential barrier to breast conservation utilization. Numerous phase III clinical trials were
conducted randomizing women post lumpectomy to RT vs. observation aimed at identifying which
cases did not derive a significant RT benefit. No such subsets of breast cancer patients were
consistently identified, thereby solidifying the standard that breast conservation required
both lumpectomy and RT. Two meta-analyses by the Early Breast Cancer Trialists Collaborative
Group (EBCTCG) in 2005 and 2011 further reinforced the value of breast RT post lumpectomy by
examining the relationship of local recurrence and breast cancer mortality relative to the
use of breast RT post lumpectomy. In each analysis, it found for axillary node negative
breast cancer patients undergoing breast conservation a small but consistent increase in
breast cancer mortality when breast radiotherapy was omitted. As a result, breast RT after
lumpectomy has become an established paradigm for breast conservation for early stage breast
cancer and is recommended by the NCCN 2018 guidelines (as it has for nearly two decades) that
are commonly used today by clinicians and health systems alike. The landscape of early stage
breast cancer has changed dramatically over the past three decades since the establishment of
breast conservation. Widespread screening with mammography has led to the diagnosis of
smaller and earlier stage disease. All breast cancers are now routinely characterized by
their hormone sensitivity based on the presence of estrogen and progesterone receptors on
tumor cells within the biopsy or surgical specimen and presence of HER2 (human epidermal
growth factor receptor 2) which has provided an additional means of stratifying breast cancer
into distinct prognostic groups. Small, node negative invasive breast cancer that is hormone
sensitive (HS) and HER2-negative has a lower overall recurrence rate (local, regional, and
distant) than breast cancers characterized by more adverse clinical pathologic features.
However, other than in a smaller subset of women greater than 70 years old, clinical trials
in this HS population still demonstrated unacceptable local recurrence risks long term after
lumpectomy alone emphasizing that clinical and pathologic features are insufficient for
consistently identifying when RT can safely be omitted.
A Phase III Clinical Trial Comparing Trastuzumab Given Concurrently With Radiation Therapy and Radiation Therapy Alone for Women With HER2-Positive Ductal Carcinoma In Situ Resected by Lumpectomy
PRIMARY OBJECTIVES:
I. To determine the value of trastuzumab given during radiation therapy (RT) compared to RT
alone in preventing subsequent occurrence of ipsilateral breast cancer recurrence,
ipsilateral skin cancer recurrence, or ipsilateral ductal carcinoma in situ (IIBCR-SCR-DCIS)
in women with human epidermal growth factor receptor 2 (HER2)-positive DCIS resected by
lumpectomy.
SECONDARY OBJECTIVES:
I. Determine the value of trastuzumab given during RT compared to RT alone in prolonging
invasive or DCIS disease-free survival (IDFS)-DCIS.
II. Determine the value of trastuzumab given during RT compared to RT alone in increasing
invasive or DCIS recurrence-free interval.
III. Determine the value of trastuzumab given during RT compared to RT alone in improving
regional or distant recurrence.
IV. Determine the value of trastuzumab given during RT compared to RT alone in improving the
incidence of contralateral invasive or DCIS breast cancer.
V. Determine the value of trastuzumab given during RT compared to RT alone in improving
survival.
VI. To explore the effect of trastuzumab on ovarian function.
TERTIARY OBJECTIVES:
I. To determine if the benefit of trastuzumab added to RT will be significantly higher in
v-myc avian myelocytomatosis viral oncogene homolog (cMYC)-amplified tumors than in the cMYC
non-amplified subset.
II. To determine if the benefit of trastuzumab added to RT will be less in tumors with
mutations in the phosphatidylinositol 3 (PI3) kinase gene than in tumors without PI3 kinase
gene mutations.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients undergo standard whole breast irradiation (WBI) over 5-6 weeks.
ARM II: Patients receive trastuzumab intravenously (IV) over 30-90 minutes once in weeks 1
and 4. Patients also undergo WBI as in Arm I.
After completion of study treatment, patients are followed up every 6 months for 5 years and
then every 12 months for 5 years.
A Phase II-R and a Phase III Trial Evaluating Both *Erlotinib (PH II-R) and Chemoradiation (PH III) as Adjuvant Treatment For Patients With Resected Head of Pancreas Adenocarcinoma
PRIMARY OBJECTIVES:
I. To determine whether the addition of erlotinib (erlotinib hydrochloride) to gemcitabine
(gemcitabine hydrochloride) adjuvant chemotherapy shows a signal for improved survival as
compared to gemcitabine alone following R0 or R1 resection of head of pancreas
adenocarcinoma (including adenocarcinoma of the head, neck, and uncinate process). (Phase
II-R) II. To determine whether the use of concurrent fluoropyrimidine and radiotherapy
following adjuvant gemcitabine hydrochloride-based chemotherapy further enhances survival
for such patients who are without evidence of progressive disease after 5 cycles of
gemcitabine based chemotherapy. (Phase III)
SECONDARY OBJECTIVES:
I. To evaluate disease-free survival of adjuvant chemotherapy followed by radiotherapy and
concurrent fluoropyrimidine for patients with resected head of pancreas adenocarcinoma who
are disease free after 5 cycles of adjuvant chemotherapy.
II. To evaluate disease-free survival of standard adjuvant gemcitabine chemotherapy with and
without erlotinib for patients with resected head of pancreas adenocarcinoma.
III. To evaluate adverse events with and without erlotinib for patients with resected head
of pancreas adenocarcinoma.
IV. To evaluate adverse events of adjuvant chemotherapy with or without radiation therapy
and concurrent fluoropyrimidine for patients with resected head of pancreas adenocarcinoma
who are disease free after adjuvant chemotherapy.
V. To evaluate preoperative cross-sectional imaging of the primary head of pancreas
adenocarcinoma in order to determine the frequency with which objective criteria of
resectability are present.
VI. To determine if patients reporting low baseline fatigue, as measured by the Functional
Assessment of Chronic Illness Therapy (FACIT)-Fatigue, predicts survival and to explore
correlations between baseline fatigue, as measured by Patient-Reported Outcomes Measurement
Information System (PROMIS), and survival.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days
1, 8, and 15. Treatment repeats every 28 days for 5 courses in the absence of disease
progression or unacceptable toxicity.
ARM II: Patients receive gemcitabine hydrochloride as in arm I and erlotinib hydrochloride
orally (PO) once daily on days 1-28. Treatment repeats every 28 days for 5 courses in the
absence of disease progression or unacceptable toxicity. (NOTE: Phase II-R erlotinib
hydrochloride randomization completed, Arm 2 closed to accrual effective 2/19/2014)
Patients with no disease progression after treatment in arm I or II are then stratified
according to their first randomization treatment arm (arm I vs arm II) and randomized to 1
of 2 additional treatment arms (arm III or IV).
ARM III: Patients receive 1 course of the same treatment that they receive in arm I or II.
ARM IV: Patients receive 1 course of the same treatment that they receive in arm I or II.
Beginning within 7-21 days after completion of chemotherapy, patients undergo radiotherapy
(3-dimensional conformal radiotherapy or intensity-modulated radiotherapy) 5 days per week
for 5.5 weeks (28 fractions). During radiotherapy, patients receive either capecitabine PO
twice daily (BID) 5 days per week or fluorouracil IV continuously for 5.5 weeks or until
radiotherapy is completed.
After completion of study treatment, patients are followed up periodically.
A Phase III Trial of Short Term Androgen Deprivation With Pelvic Lymph Node or Prostate Bed Only Radiotherapy (SPPORT) in Prostate Cancer Patients With a Rising PSA After Radical Prostatectomy
OBJECTIVES:
Primary
- To determine whether the addition of short-term androgen deprivation (STAD) to prostate
bed radiotherapy (PBRT) improves freedom from progression (FFP) (i.e., maintenance of a
prostate-specific antigen [PSA] less than the nadir+2 ng/mL, absence of clinical
failure, and absence of death from any cause) for 5 years, over that of PBRT alone in
men treated with salvage radiotherapy after radical prostatectomy.
- To determine whether STAD, pelvic lymph node radiotherapy (PLNRT), and PBRT improves
FFP over that of STAD+PBRT and PBRT alone in men treated with salvage radiotherapy
after radical prostatectomy.
Secondary
- To compare the rates of a PSA ≥ 0.4 ng/mL and rising at 5 years after randomization
(secondary biochemical failure endpoint), the development of hormone-refractory disease
(3 rises in PSA during treatment with salvage androgen-deprivation therapy), distant
metastasis, cause-specific mortality, and overall mortality.
- To compare acute and late morbidity based on Common Toxicity Criteria for Adverse
Effects (CTCAE), v. 3.0.
- To measure the expression of cell kinetic, apoptotic pathway, and angiogenesis-related
genes in archival diagnostic tissue to better define the risk of FFP, distant failure,
cause-specific mortality, and overall mortality after salvage radiotherapy for prostate
cancer, independently of conventional clinical parameters now used.
- To quantify blood product-based proteomic and genomic (single nucleotide polymorphisms)
patterns and urine-based genomic patterns before and at different times after treatment
to better define the risk of FFP, distant failure, cause-specific mortality, and
overall mortality after salvage radiotherapy for prostate cancer, independently of
conventional clinical parameters now used.
- To assess the degree, duration, and significant differences of disease-specific
health-related quality of life (HRQOL) decrements among treatment arms.
- To assess whether mood is improved and depression is decreased with the more aggressive
therapy if it improves FFP.
- To collect paraffin-embedded tissue blocks, serum, plasma, urine, and buffy coat cells
for future translational research analyses.
Tertiary
- To assess whether an incremental gain in FFP and survival with more aggressive therapy
outweighs decrements in the primary generic domains of HRQOL (i.e., mobility, self
care, usual activities, pain/discomfort, and anxiety/depression).
- To evaluate the cost-utility of the treatment arm demonstrating the most significant
benefit (in terms of the primary outcome) in comparison with other widely accepted
cancer and non-cancer therapies.
- To assess associations between serum levels of beta-amyloid and measures of cognition
and mood and depression.
- An exploratory aim is to assess the relationship(s) between the American Urological
Association Symptom Index (AUA SI) and urinary morbidity using the CTCAE v. 3.0 grading
system.
OUTLINE: Patients are stratified according to seminal vesicle involvement (yes vs no),
prostatectomy Gleason score (≤ 7 vs 8-9), pre-radiotherapy PSA (≥ 0.1 and ≤ 1.0 ng/mL vs >
1.0 and < 2.0 ng/mL), and pathology stage (pT2 and margin negative vs all others). Patients
are randomized to 1 of 3 treatment arms.
- Arm I (prostate bed radiotherapy [PBRT] alone): Patients undergo PBRT once daily, 5
days a week, Monday through Friday, for approximately 7-8 weeks (36 to 39 fractions).
- Arm II (PBRT and short-term androgen-deprivation [STAD]): Beginning 2 months before the
start of PBRT, patients undergo STAD, using a combination of antiandrogen and
luteinizing hormone-releasing hormone (LHRH) agonist therapy, for a total of 4-6
months. Patients receive antiandrogen therapy comprising either oral flutamide 3 times
daily or oral bicalutamide once daily for at least 4 months (started within 1-14 days
prior to the LHRH agonist and ending the last day of radiotherapy ± 14 days). Patients
receive LHRH agonist injection beginning concurrently with or 2 weeks after the start
of antiandrogen therapy. LHRH agonist injection consists of analogs approved by the FDA
(or by Health Canada for Canadian institutions) (e.g., leuprolide, goserelin,
buserelin, or triptorelin) and may be given in any possible combination (may be given
as a single 4-month injection and one to two 1-month injection[s], two 3-month
injections, or a 6-month injection), such that the total LHRH agonist treatment time is
4-6 months. Approximately 2 months after beginning of STAD, patients undergo PBRT as in
arm I.
- Arm III (Pelvic lymph node radiotherapy [PLNRT], PBRT, and STAD): Beginning 2 months
before the start of radiotherapy, patients receive STAD therapy as in arm II.
Approximately 2 months after beginning of STAD, patients undergo PBRT and PLNRT once
daily, 5 days a week, Monday through Friday, for approximately 5 weeks (25 fractions)
followed by PBRT only once daily, 5 days a week for approximately 2-3 weeks (11-14
fractions).
Patients complete the American Urological Association Symptom Index (AUA SI) questionnaire
prior to protocol treatment, at week 6 of radiotherapy, and then periodically after
completion of study therapy.
After completion of study therapy, patients are followed up every 3 months for 1 year, every
6 months for 4 years, and then annually thereafter.
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