A Randomized Phase II Pilot Study Prospectively Evaluating Treatment for Patients Based on ERCC1(Excision Repair Cross-Complementing 1) for Advanced/Metastatic Esophageal, Gastric or Gastroesophageal Junction (GEJ) Cancer
OBJECTIVES:
- To assess progression-free survival of high-excision repair cross-complementing 1(ERCC1)
patients with advanced or metastatic cancer of the esophagus, stomach, or
gastroesophageal junction (GEJ) treated with FOLFOX comprising oxaliplatin, leucovorin
calcium, and fluorouracil compared to those treated with irinotecan hydrochloride plus
docetaxel.
- To assess progression-free survival of low-ERCC1 patients with advanced or metastatic
cancer of the esophagus, stomach, or GEJ treated with FOLFOX compared to those treated
with irinotecan hydrochloride plus docetaxel.
- To assess progression-free survival of low-ERCC1 patients with advanced or metastatic
cancer of the esophagus, stomach, or GEJ treated with FOLFOX compared to high-ERCC1
patients treated with FOLFOX.
- To assess overall survival of and toxicities in each of the two treatment arms in this
group of patients.
- To assess the response probability (confirmed and unconfirmed, complete and partial
responses) in the subset of patients with measurable disease in each of the two
treatment arms.
- To explore whether there is evidence of interaction between treatment arm and ERCC1
expression in this group of patients. (Exploratory)
- To bank tissue and blood for future translational medicine studies; a) To explore the
relationship of ERCC-1 and ERCC-2 single nucleotide polymorphism (SNP) genotypes with
clinical outcome in these patients; and b) To explore the association between germline
variations in these SNPs and ERCC-1 mRNA expression in these patients. (Exploratory)
OUTLINE: This is a multicenter study. Patients are stratified according to ERCC1 expression
(high [≥ 1.7] vs low [< 1.7]), and disease site (esophageal vs gastric/gastroesophageal
junction). Patients are randomized to 1 of 2 treatment arms.
- Arm I (FOLFOX): Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV
over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-2. Courses repeat
every 14 days in the absence of disease progression or unacceptable toxicity.
- Arm II: Patients receive irinotecan hydrochloride IV over 90 minutes and docetaxel IV
over 30-60 minutes on days 1 and 8. Courses repeat every 21 days in the absence of
disease progression or unacceptable toxicity.
Blood and tumor tissue samples may be collected for ERCC1 expression analysis and future
research studies.
After completion of study treatment, patients are followed up every 3 months for up to 3
years.
A Dose Finding Study Followed by Phase II Randomized, Placebo-Controlled Study of Veliparib (ABT-888) Added to Chemoradiotherapy With Carboplatin and Paclitaxel for Unresectable Stage III Non-small Cell Lung Cancer (NSCLC), (NCI Study Number 8811)
PRIMARY OBJECTIVES:
I. To establish the maximum tolerated dose (MTD) and the recommended phase II dose of ABT-888
(veliparib) when given concurrently with standard carboplatin/paclitaxel and radiotherapy in
patients with unresectable stage III non-small cell lung cancer (NSCLC). (Phase I) II. To
assess whether carboplatin/paclitaxel plus ABT-888 compared with carboplatin/paclitaxel plus
placebo improves progression-free survival (PFS) in patients with unresectable stage III
NSCLC. (Phase II) III. To compare overall survival (OS) in patients treated with
carboplatin/paclitaxel and radiotherapy plus ABT-888 to those treated with carboplatin,
paclitaxel and radiotherapy plus placebo. (Phase II) IV. To assess the response rate
(confirmed and unconfirmed, complete and partial responses) and disease control rate in the
subset of patients with measurable disease by Response Evaluation Criteria in Solid Tumors
(RECIST) criteria. (Phase II) V. To assess the safety and toxicity profile of the regimen.
(Phase II)
SECONDARY OBJECTIVES:
I. To collect tumor tissue from pretreatment biopsies (archival samples) for biomarker
studies, including poly (ADP-ribose) polymerase 1 (PARP) activity by measuring the levels of
poly-ADP-ribose, gamma-H2A histone family, member X (gamma-H2AX), and messenger ribonucleic
acid (mRNA) expression levels of deoxyribonucleic acid (DNA) repair enzymes such as excision
repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1)/x-ray
repair complementing defective repair in Chinese hamster cells 1 (XRCC1).
II. To collect blood samples for evaluation of gamma-H2AX (circulating tumor cells) and other
relevant future studies.
OUTLINE: This is a phase I, dose-escalation study of veliparib followed by a randomized phase
II study.
PHASE I:
INDUCTION THERAPY: Patients undergo 3-dimensional conformal radiation therapy (3D-CRT) once
daily (QD), 5 days a week, for 6 weeks. Patients also receive veliparib orally (PO) twice
daily (BID) on days 1-43 and carboplatin intravenously (IV) over 30 minutes and paclitaxel IV
over 1 hour on days 1, 8, 15, 22, 36, and 43 in the absence of disease progression or
unacceptable toxicity. Patients without disease progression after completion of
chemoradiotherapy undergo consolidation therapy.
CONSOLIDATION THERAPY: Beginning within 4-6 weeks of chemotherapy and radiation therapy,
patients receive veliparib PO BID on days 1-7 (course 1) and 22-28 (course 2) and carboplatin
IV over 30 minutes and paclitaxel IV over 3 hours on day 1 and on day 22 of course 2.
Treatment repeats every 21 days for 2 courses in the absence of disease progression or
unacceptable toxicity.
PHASE II: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients undergo 3D-CRT and receive veliparib, carboplatin, and paclitaxel as in Phase
I induction and consolidation therapy.
ARM II: Patients undergo 3D-CRT as in arm I. Patients also receive placebo PO BID on days
1-43 and carboplatin and paclitaxel as in Phase I. Within 4-6 weeks after completion of
chemotherapy and radiation therapy, patients receive placebo on days 1-7 and carboplatin and
paclitaxel as in Phase I.
After completion of study treatment, patients are followed up every 4 months for first 2
years and then every 6 months until 5 years.
A Randomized Phase I/II Study of Optimal Induction Therapy of Bortezomib, Dexamethasone and Lenalidomide With or Without Elotuzumab (NSC-764479) for Newly Diagnosed High Risk Multiple Myeloma (HRMM)
PRIMARY OBJECTIVES:
I. To determine the appropriate Phase II dose of elotuzumab to use in combination with
lenalidomide, bortezomib, and dexamethasone for patients with multiple myeloma. (Phase I) II.
To assess whether incorporation of the novel agent elotuzumab into the treatment algorithm of
high-risk multiple myeloma (HRMM) will improve progression-free survival (PFS). (Phase II)
III. To estimate the frequency and severity of toxicities of this treatment strategy in this
patient population. (Phase II)
OUTLINE: This is a phase I, dose-escalation study of elotuzumab, followed by a phase II,
randomized study.
PHASE I:
INDUCTION: Patients receive bortezomib subcutaneously (SC) or intravenously (IV) on days 1,
4, 8, and 11; lenalidomide orally (PO) once daily (QD) on days 1-14; and dexamethasone PO or
IV on days 1, 2, 4, 5, 8, 9, 11, and 12 (and on day 15 of courses 1 and 2 only). Patients
also receive elotuzumab IV on days 1, 8, and 15 of courses 1 and 2 and on days 1 and 11 of
courses 3-8. Treatment repeats every 21 days for 8 courses in the absence of disease
progression or unacceptable toxicity.
MAINTENANCE: Patients receive bortezomib SC or IV on days 1, 8, and 15; lenalidomide PO QD on
days 1-21; dexamethasone PO on days 1, 8, and 15; and elotuzumab IV on days 1 and 15.
Treatment repeats every 28 days in the absence of disease progression or unacceptable
toxicity.
PHASE II: Patients are randomized to 1 of 2 treatment arms.
ARM I:
INDUCTION: Patients receive bortezomib SC or IV on days 1, 4, 8, and 11; lenalidomide PO QD
on days 1-14; and dexamethasone PO or IV on days 1, 2, 4, 5, 8, 9, 11, and 12. Treatment
repeats every 21 days for 8 courses in the absence of disease progression or unacceptable
toxicity (patients who received a course of chemotherapy prior to registration will begin
protocol treatment with course 2 and receive a total of 7 courses of protocol therapy).
MAINTENANCE: Patients receive bortezomib SC or IV on days 1, 8, and 15; lenalidomide PO QD on
days 1-21; and dexamethasone PO on days 1, 8, and 15. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.
ARM II:
INDUCTION: Patients receive bortezomib, lenalidomide, and dexamethasone as in Arm I. Patients
also receive elotuzumab IV on days 1, 8, and 15 of courses 1 and 2 and on days 1 and 11 of
courses 3-8. Treatment repeats every 21 days for 8 courses in the absence of disease
progression or unacceptable toxicity.
MAINTENANCE: Patients receive bortezomib, lenalidomide, and dexamethasone as in Arm I.
Patients also receive elotuzumab IV on days 1 and 15. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for up to 6
years.
A Phase II Randomized Study Comparing Two Doses of Carfilzomib (NSC-756640) With Dexamethasone for Multiple Myeloma Patients With Relapsed or Refractory Disease
PRIMARY OBJECTIVES:
I. To evaluate and compare progression free survival (PFS) of two different doses of
carfilzomib with dexamethasone in multiple myeloma (MM) patients with relapsed and/or
refractory disease.
SECONDARY OBJECTIVES:
I. To evaluate and compare response rates (RR) for each arm. II. To evaluate response rates
(RR) for patients that relapse on low dose carfilzomib and subsequently cross-over to high
dose carfilzomib.
III. To evaluate the safety of this combination for this patient population. IV. To evaluate
overall survival (OS).
TERTIARY OBJECTIVES:
I. To explore the molecular variability in MM cells obtained from extramedullary bone marrow
relapse sites.
II. To explore the role of positron emission tomography (PET) scanning in assessing disease
burden and as a tool to assess treatment response.
III. To explore changes in left ventricular ejection fraction (LVEF) in patients with
relapsed or refractory multiple myeloma treated with low dose carfilzomib or high dose
carfilzomib plus dexamethasone.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive dexamethasone intravenously (IV) and low-dose carfilzomib IV over
2-10 minutes on days 1, 2, 8, 9, 15, and 16. Patients with progression cross-over to Arm II.
ARM II: Patients receive dexamethasone IV and high-dose carfilzomib IV over 30 minutes on
days 1, 2, 8, 9, 15, and 16.
Note that for the first course of treatment on both arms carfilzomib is given at a reduced
rate to assess toxicity.
In both arms, treatment repeats every 28 days for up to 12 courses in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 3 years
from initial registration.
A Randomized Phase II Study of Co-Expression Extrapolation (COXEN) With Neoadjuvant Chemotherapy for Localized, Muscle-Invasive Bladder Cancer
The COXEN program will not select a patient's therapy, but the type of chemotherapy that
he/she will receive will be randomly decided. The patient's response to chemotherapy will be
used to test the usefulness of the COXEN program, which is the main goal of this trial. Other
potential tests to predict a patient's response to chemotherapy will also be evaluated. In
this study, the patient may receive the treatment in Arm 1 (gemcitabine and cisplatin) or the
treatment in Arm 2 [methotrexate, vinblastine, doxorubicin, cisplatin, and filgrastim (or
pegfilgrastim)]. There will be about 230 people taking part in this study (115 in each arm).
Randomized Phase II Study of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF Mutant Metastatic Colorectal Cancer
PRIMARY OBJECTIVES:
I. To evaluate the progression-free survival (PFS) of v-raf murine sarcoma viral oncogene
homolog B (BRAF) mutant metastatic colorectal cancer patients treated with irinotecan
(irinotecan hydrochloride), cetuximab, and vemurafenib, compared to a control arm of
irinotecan and cetuximab.
SECONDARY OBJECTIVES:
I. To evaluate the frequency and severity of toxicity associated with each of the treatment
arms in this patient population.
TERTIARY OBJECTIVES:
I. To evaluate overall survival (OS) in treatment Arms 1 and 2. II. To evaluate the overall
response rate (ORR), including confirmed and unconfirmed, complete and partial response, in
treatment Arms 1 and 2 in the subset of patients with measurable disease.
III. To estimate rates of OS, ORR, and PFS in patients who register to Arm 3 after disease
progression on Arm 1.
IV. To evaluate low-frequency Kirsten rat sarcoma viral oncogene homolog (KRAS) or
neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) mutations as detected by high-depth
sequencing as predictive biomarkers of efficacy.
V. To evaluate phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha
(PIK3CA) pathway activation through PIK3CA mutations or phosphatase and tensin homolog
(PTEN) protein loss as a predictive biomarker of innate resistance to this regimen.
VI. To evaluate gene expression signatures from screened patients with v-raf murine sarcoma
viral oncogene homolog B wild type (BRAFWT) and BRAFV600E tumors.
VII. To provide validation of BRAF immunohistochemistry (IHC) using complementary sequencing
methodology from screened patients with BRAFWT and BRAFV600E tumors.
VIII. To confirm the estimated sensitivity of detectable BRAF V600E circulating cell-free
deoxyribonucleic acid (DNA) as a non-invasive biomarker for BRAF V600E mutation as detected
by IHC in the primary tumor.
IX. To correlate radiographic tumor response with change in quantification of BRAFV600E
alleles in circulating cell-free DNA.
X. To monitor for known mechanism of acquired resistance to epidermal growth factor receptor
(EGFR) inhibition in circulating cell-free DNA (KRAS, NRAS mutations).
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive cetuximab intravenously (IV) and irinotecan hydrochloride IV on days
1 and 14. Courses repeat every 28 days in the absence of disease progression or unacceptable
toxicity. Patients with disease progression may cross over to Arm II.
ARM II: Patients receive cetuximab and irinotecan hydrochloride as in Arm I and vemurafenib
orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of
disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 2-6 months for 3 years.
Not recruiting | Colon / Rectal Cancer | Multisite
A Biomarker-Driven Master Protocol for Previously Treated Squamous Cell Lung Cancer (Lung-Map)
PRIMARY OBJECTIVES:
Screening component:
I. To establish a National Clinical Trials Network (NCTN) mechanism for genomically screening
large but homogeneous cancer populations and subsequently assigning and accruing
simultaneously to a multi-sub-study ?Master Protocol.? II. To evaluate the screen success
rate defined as the percentage of screened patients that register for a therapeutic
sub-study.
Sub-study-specific Objectives:
Design #1: Phase II/III Design:
III. To evaluate if there is sufficient evidence to continue to the Phase III component of
the sub-study by comparing investigator-assessed progression-free survival (IA-PFS) between
investigational therapy versus standard therapy (SoC) in patients with advanced stage
refractory squamous cell carcinoma (SCCA) of the lung. (Phase II) IV. To determine if there
is both a statistically and clinically-meaningful difference in IA-PFS among advanced stage
refractory SCCA of the lung randomized to receive investigational therapy versus SoC. (Phase
III) V. To compare overall survival (OS) in patients with advanced stage refractory SCCA of
the lung randomized to investigational therapy versus SoC. (Phase III)
Design #2: Phase II followed by Phase III (Sequential Phase II to Phase III):
VI. To evaluate the objective response rate (confirmed and unconfirmed, complete and
partial). (Phase II) VII. To determine if there is both a statistically and
clinically-meaningful difference in IA-PFS among advanced stage refractory SCCA of the lung
randomized to receive investigational therapy versus SoC. (Phase III) VIII. To compare
overall survival (OS) in patients with advanced stage refractory SCCA of the lung randomized
to investigational therapy versus SoC. (Phase III)
SECONDARY OBJECTIVES:
Sub-study-specific Objectives:
Design #1: Phase II/III Design:
I. To compare response rates (confirmed and unconfirmed, complete and partial responses)
among patients randomized to receive investigational therapy versus SoC. (Phase II) II. To
evaluate the frequency and severity of toxicities associated with investigational therapy
versus SoC. (Phase II) III. To evaluate the duration of response (DoR) among patients who
achieve a complete response (CR) or a partial response (PR) by Response Evaluation Criteria
in Solid Tumors (RECIST) (1.1). (Phase II) III. To compare the response rates (confirmed and
unconfirmed, complete and partial) among patients randomized to receive investigational
therapy versus SoC. (Phase III) IV. To evaluate the frequency and severity of toxicities
associated with investigational therapy versus SoC. (Phase III)
Design #2: Phase II followed by Phase III (Sequential Phase II to Phase III):
V. To evaluate PFS and OS with investigational therapy. (Phase II) VI. To evaluate the DoR
among patients who achieve a CR or PR (confirmed and unconfirmed) by RECIST 1.1. (Phase II)
VII. To evaluate the frequency and severity of toxicities associated with investigational
therapy. (Phase II) VIII. To compare the response rates (confirmed and unconfirmed, complete
and partial) among patients randomized to receive investigational therapy versus SoC. (Phase
III) IX. To evaluate the frequency and severity of toxicities associated with investigational
therapy versus SoC. (Phase III)
TERTIARY OBJECTIVES:
I. To evaluate the treatment arm randomization acceptance rate (TARAR) within each treatment
arm of each sub-study defined as the percentage of patients randomized to a treatment arm
that receive any protocol treatment. (Design #1: Phase II/III Design) II. To identify
additional predictive tumor/blood biomarkers that may modify response or define resistance to
the targeted therapy (TT)/targeted therapy combination (TTC) beyond the chosen biomarker for
biomarker-driven sub-studies.
III. To evaluate potentially predictive biomarkers for non-match therapy (NMT) in the
non-match studies.
IV. To identify potential resistance biomarkers at disease progression. V. To establish a
tissue/ blood repository from patients with refractory SCCA of the lung.
OUTLINE: Patients are assigned to a biomarker-driven targeted therapy phase II study. If the
objectives response rate observed is judged sufficient, patients proceed to a randomized
phase III trial and are randomized to biomarker-driven targeted therapy or standard of care.
S1400A: (CLOSED TO ACCRUAL 12/18/2015) Patients with tumors that do not match one of the
currently active drug-biomarker combinations or did not meet the eligibility requirements for
that bio-marker driven sub-study are assigned to Arm I. Upon evidence of progression
following discontinuation of 12 months of treatment, patients may restart treatment for up to
12 months with the same treatment guidelines followed during the initial 12-month treatment
period (Arm III).
ARM I: (CLOSED TO ACCRUAL 12/18/2015) Patients receive anti-B7H1 monoclonal antibody MEDI4736
intravenously (IV) over 60 minutes on day 1. Treatment repeats every 14 days for 12 months in
the absence of disease progression or unacceptable toxicity.
ARM II (CLOSED TO ACCRUAL 4/2015): Patients receive docetaxel IV on day 1. Courses repeat
every 21 days in the absence of disease progression or unacceptable toxicity. (closed to
accrual with Revision #2 4/22/15)
ARM III: For patients assigned to Arm 1, MEDI4736: Upon evidence of progression following
discontinuation of 12 months of treatment, patients may restart treatment with Arm 3,
MEDI4736 for up to 12 months with the same treatment guidelines followed during the initial
12-month treatment period. Patients will only be able to restart treatment once; thus a
maximum of two 12-month periods will be allowed. Patients receive anti-B7H1 monoclonal
antibody MEDI4736 intravenously (IV) over 60 minutes on day 1. Treatment repeats every 14
days for 12 months in the absence of disease progression or unacceptable toxicity.
S1400B (CLOSED TO ACCRUAL 12/12/2016): Patients with tumors positive for phosphoinositide
3-kinase (PI3KCA) are assigned to Arm I. Patients currently on Arm 2, docetaxel will be given
the option to re-register to Arm 3, GCD-0032 after disease progression on current treatment
(Arm III).
ARM I: Patients receive taselisib orally (PO) daily on days 1-21. Courses repeat every 21
days in the absence of disease progression or unacceptable toxicity.
ARM II (CLOSED TO ACCRUAL 12/18/2015): Patients receive docetaxel IV on day 1. Courses repeat
every 21 days in the absence of disease progression or unacceptable toxicity. (closed to
accrual with Revision #3 12/18/2015)
ARM III: Re-Registration Treatment with GDC-0032 (Taselisib) Upon progression patients in Arm
2 may be eligible for Re-Registration to receive GDC-0032. Patients receive taselisib orally
(PO) daily on days 1-21. Courses repeat every 21 days in the absence of disease progression
or unacceptable toxicity.
S1400C (CLOSED TO ACCRUAL 09/01/2016): Patients with tumors positive for cyclin dependent
kinase 4 (CDK4), cyclin D1 (CCND1), cyclin D2 (CCND2), and cyclin D3 (CCND3) are assigned to
Arm I. Patients currently on Arm 2, docetaxel will be given the option to re-register to Arm
3, palbociclib, after disease progression on current treatment (Arm III).
ARM I: Patients receive palbociclib PO on days 1-21. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.
ARM II (CLOSED TO ACCRUAL 12/18/2015): Patients receive docetaxel IV on day 1. Courses repeat
every 21 days in the absence of disease progression or unacceptable toxicity. (closed to
accrual with Revision #3 12/18/2015)
ARM III: Re-Registration Treatment with Palbociclib. Upon progression patients in Arm 2 may
be eligible for Re-Registration to receive palbociclib. Patients receive palbociclib PO on
days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable
toxicity.
S1400D (CLOSED TO ACCRUAL 10/31/2016): Patients with tumors positive for fibroblast growth
factor receptor (FGFR) 1, FGFR2, and FGFR3 are assigned to Arm I. Patients currently on Arm
2, docetaxel will be given the option to re-register to Arm 3, AZD4547, after disease
progression on current treatment (Arm III).
ARM I: Patients receive FGFR inhibitor AZD4547 PO BID on days 1-21. Courses repeat every 21
days in the absence of disease progression or unacceptable toxicity.
ARM II (CLOSED TO ACCRUAL 12/18/2015): Patients receive docetaxel IV on day 1. Courses repeat
every 21 days in the absence of disease progression or unacceptable toxicity. (closed to
accrual with Revision #3 12/18/2015)
ARM III: Re-Registration Treatment with AZD4547. Upon progression patients in Arm 2 may be
eligible for Re-Registration to receive AZD4547. Patients receive FGFR inhibitor AZD4547 PO
BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.
S1400E (CLOSED TO ACCRUAL 11/25/2014): Patients with tumors positive for met proto-oncogene
(MET) are randomized to 1 of 2 treatment arms. (permanently closed to accrual on 11/25/14)
ARM I: Patients receive rilotumumab IV on day 1 and erlotinib hydrochloride PO daily on days
1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable
toxicity.
ARM II: Patients receive erlotinib hydrochloride PO daily on days 1-21. Courses repeat every
21 days in the absence of disease progression or unacceptable toxicity.
S1400F: Patients with disease progression during or after prior anti-PD-1 or anti-PD-L1
antibody monotherapy as their most recent line of treatment receive durvalumab (IV over 60
minutes) and tremelimumab (IV over 60 minutes) on day 1 for courses 1-4 and durvalumab IV
alone on day 1 of course 5 and subsequent courses until disease progression or unacceptable
toxicity. Courses repeat every 28 days.
S1400G: Patients with tumors positive for homologous recombination repair deficiency receive
talazoparib PO daily on days 1-21. Courses repeat every 21 days in the absence of disease
progression or unacceptable toxicity.
S1400I: Patients with tumors that do not match one of the currently active drug-biomarker
combinations or did not meet the eligibility requirements for that bio-marker driven
sub-study are randomized to 1 of 2 treatment arms.
ARM I: Patients receive nivolumab IV over 30 minutes on day 1 and ipilimumab IV over 60
minutes on day 1 of every third course. Courses repeat every 14 days in the absence of
disease progression or unacceptable toxicity.
ARM II: Patients receive nivolumab IV over 30 minutes on day 1. Courses repeat every 14 days
in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, all patients are followed up periodically for up to 3
years from date of screening registration.
A Phase II and Pilot Trial of PD-1 Blockade With Pembrolizumab (MK-3475) in Patients With Resectable or Unresectable Desmoplastic Melanoma (DM)
PRIMARY OBJECTIVES:
I. To evaluate the pathologic complete response rate (pCR) in patients with resectable
desmoplastic melanoma treated with neoadjuvant pembrolizumab (MK-3475). (Cohort A) II. To
evaluate the complete response rate (confirmed and unconfirmed) in patients with unresectable
desmoplastic melanoma treated with pembrolizumab (MK-3475). (Cohort B)
SECONDARY OBJECTIVES:
I. To estimate the 9 week response rate (RR) (unconfirmed complete and partial responses)
among patients with measurable disease. (Cohort A) II. To estimate the median overall
survival (OS). (Cohort A) III. To evaluate safety and tolerability of pembrolizumab (MK-3475)
in the neoadjuvant setting. (Cohort A) IV. To estimate the median progression-free survival
(PFS). (Cohort B) V. To estimate the median overall survival (OS). (Cohort B) VI. To evaluate
safety and tolerability of pembrolizumab (MK-3475) in this setting. (Cohort B)
OTHER OBJECTIVES:
I. To evaluate the hypothesis that higher mutational load in the patient derived baseline
tumor biopsy samples is associated with higher pathologic complete response (pCR).
II. To evaluate T cell infiltration into the tumors and circulating tumor deoxyribonucleic
acid (DNA) profile from blood samples in DM patients and correlate with response to
programmed cell death protein 1 (PD-1) blockade.
III. To evaluate the clonality of tumor infiltrating T cells in DM patients and correlate
with response to PD-1 blockade.
IV. To evaluate adaptive immune resistant mechanism in DM tumors.
OUTLINE: Patients are enrolled to 1 of 2 cohorts.
COHORT A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1.
Treatment repeats every 21 days for up to 3 cycles. Patients with potentially resectable
disease undergo surgery. Patients with tumor progression and unresectable disease may receive
one additional cycle of pembrolizumab.
COHORT B: Patients with unresectable disease receive pembrolizumab IV over 30 minutes on day
1. Treatment repeats every 21 days for up to 34 cycles in the absence of disease progression
or toxicity.
Patients undergo computed tomography (CT) scan and may undergo position emission tomography
(PET) and magnetic resonance imaging (MRI) throughout the study. Patients also undergo blood
sample collection at screening and tumor biopsy throughout the study.
After completion of study treatment, patients are followed up at 6 weeks after the last dose,
then every 12 weeks to the end of the first year, then every 6 months to the end of the fifth
year after registration. After progression, patients are followed every 6 months for up to 2
years from the date of registration, then annually thereafter until 5 years from
registration.
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
DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors
PRIMARY OBJECTIVES:
I. To evaluate the Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
overall response rate (ORR) in subsets of patients with advanced rare cancers treated with
ipilimumab plus nivolumab combination immunotherapy.
II. To evaluate the overall response rate (ORR) in patients with gestational trophoblastic
tumors treated with ipilimumab plus nivolumab combination immunotherapy.
III. To evaluate the RECIST v1.1 overall response rate (ORR) in patients PD-L1 amplified
cancers treated with nivolumab immunotherapy.
SECONDARY OBJECTIVES:
I. To evaluate toxicities in each cohort. II. To estimate overall survival (OS),
progression-free survival (PFS), clinical benefit rate; and to estimate immune related
(i)RECIST ORR (iORR), and iRECIST PFS (iPFS) across cohorts and within each cohort.
OUTLINE: Patients are assigned to 1 of 2 arms.
ARM I (ALL COHORTS EXCEPT THE PD-L1 AMPLIFIED COHORT): Patients receive nivolumab
intravenously (IV) over 30 minutes on days 1, 15, and 29 and ipilimumab IV over 60 minutes on
day 1. Treatment repeats every 42 days for up to 17 cycles (2 years) in the absence of
disease progression or unacceptable toxicity. Patients who complete 17 cycles (2 years) of
therapy, may continue receiving the same treatment with nivolumab and ipilimumab, or receive
nivolumab once every 14 or 28 days (2 weeks or 4 weeks) per physician discretion in the
absence of disease progression or unacceptable toxicity. Patients who stop treatment prior to
the completion of 17 cycles of therapy may receive nivolumab once every 14 or 28 days (2
weeks or 4 weeks) in the absence of disease progression or unacceptable toxicity. Patients
undergo echocardiography (ECHO) during screening and on study. Patients also undergo magnetic
resonance imaging (MRI) or computed tomography (CT) throughout the trial. Additionally,
patients undergo blood sample collection throughout the trial.
ARM II (PD-L1 AMPLIFIED COHORT): Patients receive nivolumab IV over 30 minutes on days 1, 15
and 29. Treatment repeats every 42 days for up to 17 cycles (2 years) in the absence of
disease progression or unacceptable toxicity. After 17 cycles (2 years) of therapy, patients
may receive nivolumab once every 14 or 28 days (2 weeks or 4 weeks) in the absence of disease
progression or unacceptable toxicity. Patients undergo ECHO during screening and on study.
Patients also undergo MRI or CT throughout the trial. Additionally, patients undergo blood
sample collection throughout the trial.
After completion of study treatment, patients are followed up for 10 years from registration.
S1613, A Randomized Phase II Study of Trastuzumab and Pertuzumab (TP) Compared to Cetuximab and Irinotecan (CETIRI) in Advanced/Metastatic Colorectal Cancer (mCRC) With HER-2 Amplification
PRIMARY OBJECTIVES:
I. To evaluate the efficacy of trastuzumab and pertuzumab (TP) (Arm 1) in HER-2 amplified
metastatic colorectal cancer (mCRC) by comparing progression-free survival (PFS) on TP
compared to control arm (Arm 2) of cetuximab and irinotecan hydrochloride (irinotecan)
(CETIRI).
SECONDARY OBJECTIVES:
I. To evaluate the overall response rate (ORR), including confirmed complete and partial
response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, in treatment Arms 1
and 2.
II. To evaluate the overall survival (OS) in treatment Arms 1 and 2. III. To evaluate the
safety and toxicity of TP compared to CETIRI.
TERTIARY OBJECTIVES:
I. To estimate the rates of PFS, OS, and ORR in patients who crossover to TP (Arm 3) after
disease progression on CETIRI.
II. To bank images for future retrospective analysis. III. To evaluate if HER-2/centromeric
probe (CEP17) signal ratio and HER-2 gene copy number (GCN) are predictive of clinical
efficacy for patients receiving TP versus CETIRI.
IV. To bank tissue and blood samples for other future correlative studies from patients
enrolled on the study.
OUTLINE: Patients with HER2 gene amplification are randomized to 1 of 2 arms.
ARM I: Patients receive pertuzumab intravenously (IV) over 30-60 minutes and trastuzumab IV
over 30-120 minutes on day 1. Courses repeat every 21 days in the absence of disease
progression or unacceptable toxicity.
ARM II: Patients receive cetuximab IV over 60-120 minutes and irinotecan hydrochloride IV
over 90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression
or unacceptable toxicity. Patients with documented disease progression may optionally
crossover to Arm I.
After completion of study treatment, patients are followed up for 3 years.
A Phase II Randomized Study of Adjuvant Versus NeoAdjuvant Pembrolizumab (MK-3475) for Clinically Detectable Stage III-IV High-Risk Melanoma
PRIMARY OBJECTIVE:
I. To compare event-free survival (EFS) in participants with high-risk resectable melanoma
randomized to neoadjuvant pembrolizumab (MK-3475) with participants randomized to adjuvant
pembrolizumab (MK-3475).
SECONDARY OBJECTIVES:
I. To assess the frequency and severity of toxicities on each of the arms. II. To compare
between arms overall survival (OS), disease control at 24 weeks, locoregional control in the
surgical site(s), and total number of pembrolizumab (MK-3475) doses received.
III. On the neoadjuvant arm, to estimate the pathologic response rate, the Response
Evaluation Criteria in Solid Tumors (RECIST) 1.1 response rate (confirmed and unconfirmed
complete response [CR] and partial response [PR]), and the immune-related (i)RECIST response
rate (confirmed and unconfirmed CR and PR), before surgical resection; to compare definitions
of pathologic partial response; and to evaluate the association between pathologic response
and EFS and OS.
IV. To describe the proportion of participants on each arm who received the surgery planned
at randomization.
ADDITIONAL OBJECTIVE:
I. To bank tumor tissue and whole blood in anticipation of future correlative studies in this
participant population.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Within 17 days (preferably within 14 days) days after surgical resection, patients
receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 3
weeks for 18 cycles in the absence of disease progression or unacceptable toxicity. Patients
also undergo collection of blood throughout the study, and magnetic resonance imaging (MRI)
or computers tomography (CT) on study.
ARM II: Patients receive pembrolizumab IV over 30 minutes on day 1 every 3 weeks for 3
cycles, then undergo surgical resection within 3 weeks. Within 84 days, patients receive
pembrolizumab IV over 30 minutes every 3 weeks for 15 cycles in the absence of disease
progression or unacceptable toxicity. Patients also undergo collection of blood throughout
the study and MRI or CT on study.
After completion of study treatment, patients are followed up at 3 and 12 weeks, then every 3
months for 2 years, every 6 months for 3 years, then every 12 months for up to 10 years.
Randomized Phase II Study to Assess the Role of Nivolumab as Single Agent to Eliminate Minimal Residual Disease and Maintain Remission in Acute Myelogenous Leukemia (AML) Patients After Chemotherapy (REMAIN TRIAL)
PRIMARY OBJECTIVE:
I. To evaluate and compare the progression free survival rate after randomization in the two
treatment arms (nivolumab versus [vs.] observation).
SECONDARY OBJECTIVES:
I. To determine and compare the overall survival rates in the two arms. II. To determine and
compare the incidence of non-relapse mortality in the two arms.
III. To evaluate the toxicities of nivolumab as maintenance.
EXPLORATORY OBJECTIVES:
I. To analyze PD-L1 expression on acute myeloid leukemia (AML) cells from peripheral blood
and/or bone marrow samples at diagnosis if available and at the time of study enrollment.
II. To monitor AML minimal residual disease (MRD) by Wilms tumor 1 (WT1) polymerase chain
reaction (PCR) at enrollment and at subsequent defined time points in the nivolumab-treated
and control groups.
III. To perform an exploratory analysis on the frequencies, absolute numbers and subsets of T
cells (including regulatory T cells) in the nivolumab-treated and control groups with an
emphasis on activation markers.
IV. To perform deep sequencing of T cell receptor (TCR)-alpha and TCR-beta chains on
polyclonal T cells at baseline and at subsequent time points in the nivolumab and control
groups.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes once every 2 weeks.
Treatment repeats every 2 weeks for 46 cycles in the absence of disease progression or
unacceptable toxicity. Patients also undergo bone marrow biopsy at screening, months 3, 6,
and 12, as clinically indicated, and at the time off study. Patients also undergo collection
of blood samples at screening, weeks 9, 13, 25, and 53, and during off-study evaluation or at
time of clinically suspected relapse. Patients may undergo echocardiography (ECHO) as
clinically indicated.
ARM II: Patients undergo standard of care clinical observation for up to 2 years. Upon
disease relapse, patients may cross-over to Arm I. Patients also undergo bone marrow biopsy
at screening, months 3, 6, and 12, as clinically indicated, and during off-study evaluation.
Patients also undergo collection of blood samples at screening, weeks 9, 13, 25, and 53, and
during off-study evaluation or at time of clinically suspected relapse. Patients may undergo
ECHO as clinically indicated.
After completion of study treatment, patients are followed up periodically for 2 years, every
6 months for 1 year, and then yearly thereafter.
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