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 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.
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 Randomized Trial of Eribulin (NSC #707389) With Gemcitabine Versus Standard of Care (Physician's Choice) for Treatment of Metastatic Urothelial Carcinoma Refractory to, or Ineligible for, Anti PD1/PDL1 Therapy
PRIMARY OBJECTIVES:
I. To compare overall survival in participants with metastatic urothelial carcinoma (mUC) who
are randomized to standard treatment versus eribulin plus gemcitabine hydrochloride
(gemcitabine).
SECONDARY OBJECTIVES:
I. To compare progression-free survival (PFS) in the standard treatment arm to the
experimental treatment arm in this population.
II. To compare Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 overall response
rate (ORR), both confirmed and unconfirmed, complete and partial responses (CR and PR), in
the standard treatment arm to the experimental treatment arm in the subset of participants
with measurable disease in this population.
III. To compare duration of response (DOR) in the standard treatment arm to the experimental
treatment arm in the subset of participants with measurable disease in this population.
IV. To compare disease control rate (DCR) in the standard treatment arm to the experimental
treatment arm in the subset of participants with measurable disease in this population.
BANKING OBJECTIVE:
I. To bank specimens for future correlative studies.
OUTLINE: Patients are randomized to 1 of 3 arms.
ARM I: Patients receive 1 of the 4 standard of care chemotherapy regimens based on treating
investigator's choice: Choice A: Patients receive docetaxel intravenously (IV) on day 1.
Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Choice B: Patients receive gemcitabine IV on days 1, 8, and 15. Cycles repeat every 28 days
in the absence of disease progression or unacceptable toxicity. Choice C: Patients receive
paclitaxel IV on days 1, 8, and 15. Cycles repeat every 21 days in the absence of disease
progression or unacceptable toxicity. Choice D: Patients receive sacituzumab govitecan IV on
days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or
unacceptable toxicity.
ARM II: Patients receive eribulin IV over 2-5 minutes on days 1 and 8. Cycles repeat every 21
days in the absence of disease progression or unacceptable toxicity. (CLOSED TO ACCRUAL)
ARM III: Patients receive eribulin IV over 2-5 minutes and gemcitabine IV on days 1 and 8.
Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
All patients undergo computed tomography (CT), magnetic resonance imaging (MRI) and bone scan
throughout the trial. Patients also undergo blood and urine sample collection on the trial.
After completion of study treatment, patients are followed up every 6 months for 2 years from
the date of registration, then every 12 months until death or 3 years from the date of
registration
Phase 3 Accelerated BEP: A Randomised Phase 3 Trial of Accelerated Versus Standard BEP Chemotherapy for Patients With Intermediate and Poor-risk Metastatic Germ Cell Tumours
Bleomycin, Etoposide, Cisplatin (BEP) administered 3-weekly x 4 remains standard 1st line
chemotherapy for intermediate- and poor-risk metastatic germ cell tumours (GCTs). Cure rates
are over 90% for good-risk disease, 85% with intermediate-risk, and about 70% for poor-risk
disease. Previous strategies to improve first-line chemotherapy have failed to improve cure
rates and were more toxic than BEP. New strategies are needed for patients with intermediate
and poor-risk disease. BEP is accelerated by cycling Cisplatin and etoposide 2-weekly instead
of 3-weekly. The Australian and New Zealand Urogenital and Prostate Cancer Trials Group
(ANZUP) is conducting a trial comparing accelerated BEP with standard BEP. The aim of this
study is to determine if accelerated BEP is superior to standard BEP as first-line
chemotherapy for intermediate and poor risk metastatic GCTs.
A Randomized Phase III Trial of Induction/Consolidation Atezolizumab (NSC #783608) + SBRT Versus SBRT Alone in High Risk, Early Stage NSCLC
PRIMARY OBJECTIVE:
I. To compare overall survival (OS) in patients with inoperable, early stage non-small cell
lung cancer (NSCLC) randomized to stereotactic body radiation therapy (SBRT) with or without
atezolizumab.
SECONDARY OBJECTIVES:
I. To compare investigator-assessed progression-free survival (IA-PFS) between the arms.
II. To compare progression free survival (PFS) by blinded independent centralized review
(BIRC) between the arms in a random subset of patients.
III. To evaluate distant, locoregional, and local failure rates within each treatment arm.
IV. To evaluate the frequency and severity of toxicities within each treatment arm.
ADDITIONAL OBJECTIVE:
I. To collect specimens for banking.
HEALTH-RELATED QUALITY OF LIFE (HRQOL) OBJECTIVE:
I. To assess quality of life as measured by the European Organization for Research and
Treatment of Cancer Quality of Life (EORTC QLQ)-30 and EORTC-QLQ- Lung Cancer (LC)13 between
the arms.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1 of each
cycle. Treatment repeats every 21 days for 8 cycles in the absence of disease progression or
unacceptable toxicity. Starting on day 1 cycle 3, patients also undergo SBRT for 3-8
treatments every 2 days or once daily (QD) over 1-3 weeks. Patients undergo fludeoxyglucose
F-18 (FDG)-positron emission tomography/computed tomography (PET/CT) during screening.
Patients undergo blood sample collection and CT scans throughout the trial.
ARM B: Beginning 21 days after randomization, patients undergo SBRT for 3-8 treatments every
2 days or QD over 1-3 weeks. Patients undergo FDG-PET/CT during screening. Patients undergo
blood sample collection and CT scans throughout the trial.
After completion of study treatment, patients are followed for 5 years after randomization.
Immune Checkpoint Inhibitor Toxicity (I-CHECKIT): A Prospective Observational Study
PRIMARY OBJECTIVE:
I. To both develop and independently validate a risk prediction model for Common Terminology
Criteria for Adverse Events (CTCAE) grade 3 or higher non-hematological immune-related
adverse events (irAEs) in the first year of immune checkpoint inhibitor (ICI)-based therapy
for the treatment of solid tumors.
SECONDARY OBJECTIVES:
I. To prospectively assess the incidence of any grade of non-hematological irAEs and grade 4
hematological irAEs on ICI-based therapy.
II. To observe the trajectory of patient-reported quality of life and health preferences over
12 months.
III. To observe the trajectory of patient-reported adverse events over 12 months using serial
assessment with select Patient-Reported Outcomes version of the Common Terminology Criteria
for Adverse Events (PRO-CTCAE) measures.
IV. To measure the burden of chronic, grade 1 and 2 toxicities using methods such as toxicity
over time (ToxT).
V. To track patterns of treatment of irAEs and patterns of toxicity resolution.
TRANSLATIONAL MEDICINE OBJECTIVES:
I. To evaluate the cytokine toxicity (CYTOX) score, a composite measure derived from 11
different cytokine levels, both prior to ICI-based therapy and after 1 cycle of ICI-based
therapy as a predictive signature for the development of irAEs.
II. To establish a repository of archival tissue and blood/serum specimens for potential
predictive and/or prognostic markers of irAE risk.
ADDITIONAL OBJECTIVE:
I. To assess the feasibility of using electronic (e)PRO in a multi-center clinical trial
setting.
OUTLINE:
Patients undergo collection of a tissue sample at the start of their routine cancer
treatment. Patients complete questionnaires at the start of cancer treatment, weeks 4, 12,
24, and 52. Patients will have the option of providing blood samples at several time points
during the study.
Blue Light Cystoscopy With Cysview® Registry
Data will be captured on specific patient types undergoing Blue Light Cystoscopy with Cysview
for known or suspected non-muscle invasive bladder cancer. Specific clinical questions will
be asked.
1. What is the incremental detection rate with Blue Light Cystoscopy with Cysview over
conventional white light cystoscopy in each of the seven (7) patient populations? Does
this translate into lower recurrence/progression rate?
2. How do the six (6) tumor variables used in the European Association of Urology (EAU)
risk tables (primary/secondary, recurrence rate, size, multifocality, grade, and history
of carcinoma in situ (CIS))6 affect this incremental rate?
3. How does an abnormal cytology or positive or negative fluorescent in situ hybridization
(FISH) affect the likelihood that Blue Light Cystoscopy with Cysview will detect more
cancers than white light?
4. What are the performance characteristics of Blue Light Cystoscopy with Cysview within
eight (8) weeks of Bacillus Calmette-Guérin (BCG) with respect to improved tumor
detection and false positive rate compared to conventional white light cystoscopy?
5. What is the incremental Blue Light Cystoscopy with Cysview detection rate over random
bladder biopsies alone in patients being evaluated for routine three month restaging
(group 4) or occult disease (group 5)?
6. What are the performance characteristics of Blue Light Cystoscopy with Cysview after
repeated Blue Light Cystoscopy with Cysview evaluations with respect to improved tumor
detection, false positive rate and safety compared to conventional white light?
7. Does an abnormal urinalysis help identify patients with inflammation more likely to have
false positive Blue Light Cystoscopy with Cysview results?
8. What is the practical learning curve for becoming "proficient" with Blue Light
Cystoscopy with Cysview?
9. What is the overall false positive rate with Blue Light Cystoscopy with Cysview?
10. Can Blue Light Cystoscopy with Cysview make the resection more complete? If yes, is this
due to improved margins and/or additional tumors seen under blue light?
The Blue Light Cystoscopy with Cysview Registry is a web-based program supported by Global
Vision Technologies. Data will be captured longitudinally over five (5) years on patients
from each enrolled site. Each center will enter their respective site's patient data
electronically.
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