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
Background:Combined modality therapy with chemotherapy and radiation has become the standard of care for the treatment of patients with locally advanced NSCLC.The Cancer and Leukemia Group B (CALGB) conducted a randomized Phase II study of two cycles of induction chemotherapy followed by two additional cycles of the same drugs with concomitant radiotherapy for patients with locally advanced NSCLC. The results of this trial demonstrated similar survival rates between the 2 arms.We propose to use a backbone of standard chemoradiotherapy with carboplatin and paclitaxel to investigate the addition of oral ABT-888. ABT-888 potentiates the anti-cancer effects of various cytotoxic agents including carboplatin in preclinical studies.Objectives:To establish the MTD and the recommended Phase II dose of ABT-888 when given concurrently with standard carboplatin/paclitaxel and radiotherapy in patients with unresectable Stage III non-small cell lung cancer (NSCLC).Study Population:Patients must have histologically or cytologically-proven new diagnosis of unresectable Stage IIIA/IIIB*, non-small cell lung cancer (adenocarcinoma, bronchioloalveolar cell carcinoma, large cell carcinoma, squamous cell carcinoma, or mixed). Patients age is 18 years and over.Primary Endpoints: a. Measurable disease: 1. Lesions that can be accurately measured in at least one dimension 2. Malignant lymph nodes b. Non-measurable disease: 1. All other lesions (or sites of disease), including small lesionsDescription of Study Arms:Phase I portion:First Registration: Chemoradiation Phase 6 weeks of external beam radiation + paclitaxel + carboplatin + ABT-888 at assigned dose level. Re-evaluation and Second RegistrationConsolidation Phase (ABT-888 + carboplatin + paclitaxel) (Two 21-day cycles)Phase II portion:First Registration/Randomization: Chemoradiation Phase 6 weeks of external beam radiation + paclitaxel + carboplatin + ABT-888/placebo at assigned dose level.Re-evaluation and Second Registration:ABT-888 Carboplatin Paclitaxel (2 cycles) OR Placebo Carboplatin Paclitaxel (2 cycles) Only Arm 2 will be done at USC.Intervention:Emergency unblinding will proceed in the event of an emergency or severe adverse reaction necessitating identification of the medication for the welfare of the patient.Toxicities attributable to the study regimen will undergo dose limiting. (DLT) Patient will be removed from the study for progression of disease or symptomatic deterioration, grade 3 or worse infusion reactions and unacceptable toxicity.Follow-up:All patients will be followed until death or 5 years after registration, whichever occurs first.Statistics/Analysis:This study will initially be open in limited institutions, with an expected accrual of 10-30 patients in the Phase I portion of the trial. The estimated accrual rate for this part of the study is 2-3 patients/ month. The Phase II portion of the trial will be open Group-wide. Based on data from previous studies in similar patient populations the estimated accrual rate is 8-9 patients/month for the phase II portion of the study.Primary analyses will be performed on an intent-to-treat basis. A stratified log-rank test at the 10% level will be used to test the primary hypothesis. The final analysis will take place upon the observation of 68 progression events.
9L-14-3: A Phase 4 Safety And Efficacy Study Of Bosutinib (Bosulif) In Patients With Philadelphia Chromosome Positive Chronic Myeloid Leukemia Previously Treated With One Or More Tyrosine Kinase Inhibitors
The study drug, bosutinib is a tyrosine kinase inhibitor (TKI) that has been approved for the treatment of adult patients with Philadelphia chromosome positive chronic phase chronic myelogenous leukemia (CML) previously treated with other TKI therapy. CML is the fourth most commonly occurring adult leukemia. The transformation of CML from a deadly cancer to a chronic illness that took place over the last decade has been to the development of TKIs (inhibitors of the kinase activity of BCR-ABL1). The purpose of this phase 4 study is to fulfill the post-authorization commitment made by Pfizer to the European Medicines Agency in providing additional safety and efficacy data in approximately 150 Ph+ CML patients with high unmet medical need, including 75 chronic phase (CP), accelerated phase( AP) or BP(blastic phase) participants in the 4th or later line treatment setting. The primary objectives of this study are to estimate the 1-year (Week 52) probability of cumulative Major Cytogenetic Response (MCyR) in CP Ph+ CML patients with 1 or 2 prior lines of TKI therapy or 3 or more prior lines of TKI therapy. And to estimate the 1-year (Week 52) probability of cumulative confirmed Overall Hematological Response (OHR) in AP and BP Ph+ CML patients with any prior TKI therapy.This is a single-arm, open-label, non-randomized, multi-center Phase 4 study to evaluate bosutinib (Bosulif ) in patients with CP/AP/BP Ph+ CML whose disease has failed prior treatment with commercially available TKIs due to drug resistance or intolerance, or are otherwise contraindicated for treatment with commercially available TKIs such as imatinib, dasatinib, or nilotinib.Participants will receive bosutinib for at least 4 years from the time of first dose. Participants discontinuing bosutinib before completing at least 4 years of therapy will be followed for survival until they complete at least 4 years on study. Participants completing at least 4 years of bosutinib with continued benefit may be switched to commercially available therapy at that time. During the first 3 months of study, disease assessments will be performed weekly during the first month, then approximately every 4 weeks until Week 13. Assessments will then be performed every 3 months until Week 52, then at 6 month intervals during year 2, 3, and 4 of treatment.This study does not include any formal sample size determination. All treated Ph+ participants will be included in the efficacy analyses. Analyses will be presented by disease stage and/or line of therapy. The exploratory time-to-event endpoints of OS and PFS will be summarized using the Kaplan-Meier method or by cumulative incidence, whichever is more appropriate.
9L-13-1: Correlative Biomarker Study for MPD-RC Treatment Studies in the Philadelphia Chromosome Negative Myeloproliferative Neoplasms (MPN)
The Philadelphia chromosome negative myeloproliferative neoplasms (MPN) polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are clonal hematopoietic malignancies originating at the level of the pluripotent hematopoietic stem cell. MPNs have the potential to undergo clonal evolution and a stepwise progression that terminates in bone marrow failure due to myelofibrosis, ineffective hematopoiesis, or in transformation to acute leukemia. Recently it has been learned that a point mutation in the tyrosine kinase, Jak2, accounts for the characteristic growth factor hypersensitivity observed in MPNs, however, the molecular mechanisms that result in the etiology and progression of these neoplasms have not been fully characterized. Because of the long evolution of these neoplasms, identifying biomarkers of disease progression and the development of molecularly targeted translational therapies has been difficult.The principal objective of this study is to collect and store tissue samples from patients with myeloproliferative neoplasms (PV, PMF, and ET). Tissue samples will be used to perform a variety of biomarker studies to monitor the effects of a particular therapeutic intervention. The specimens will be obtained from study participants either at the time of diagnosis, remission, or at relapse, or other specific time points as specified by the individual treatment/research protocols.Study participants qualify to take part in this research study because they have agreed to participate in an MPD-RC treatment study for which this biomarker study is a mandatory component. Participants will be asked to participate in this study that allows for the storage of a small portion of the participants blood and bone marrow and toenail clippings for research. This study is being conducted by the Myeloproliferative Disorders Research Consortium (MPD-RC) through a grant provided by the National Cancer Institute (NCI). These samples will be frozen and securely stored at the MPD-RC Research Laboratory at the New York Blood Center in New York, New York. Participation in this study is expected to last from 2 to 4 years.
SWOG-1318 A Phase II Study of Blinatumomab (NSC-765986) and POMP (Prednisone, Vincristine, Methotrexate, 6-Mercaptopurine) for Patients >/= 65 Years of Age with Newly Diagnosed Philadelphia-Chromosome Negative (Ph-) Acute Lymphoblastic Leukemia (ALL) and of Dasatinib (NSC-732517), Prednisone and Blinatumomab for Patients >/= 65 Years of Age with Newly Diagnosed Philadelphia-Chromosome Positive (Ph+) ALL
I. To evaluate the 3-year survival rate in elderly patients with newly diagnosed
Philadelphia (Ph)-negative acute lymphoblastic leukemia (ALL) treated with blinatumomab
followed by POMP (prednisone, vincristine sulfate, methotrexate, and mercaptopurine)
II. To evaluate in a preliminary manner (feasibility study) the safety of dasatinib-steroid
based induction followed by blinatumomab treatment in combination with dasatinib followed by
dasatinib-based maintenance in patients with newly diagnosed Ph-positive ALL,
relapsed/refractory Ph-positive ALL, and Ph-like dasatinib-sensitive mutations or kinase
fusions (DSMKF) ALL (newly-diagnosed relapsed or refractory).
I. To evaluate toxicities in these patient populations treated with these regimens.
II. To estimate the rates of complete response (CR), complete remission with incomplete
count recovery (CRi) and disease-free survival in Ph-negative patients.
III. To estimate disease-free and overall survival in Ph-positive ALL and Ph-like DSMKF ALL.
IV. To estimate in each cohort the rate of minimal residual disease (MRD) negativity, and
the time to achieve MRD negativity (exploratory analysis).
V. To determine whether anti-idiotype antibodies directed against blinatumomab develop with
blinatumomab treatment in this study.
OUTLINE: Patients are assigned to 1 of 2 treatment cohorts according to Philadelphia
COHORT I (PHILADELPHIA CHROMOSOME NEGATIVE PATIENTS):
INDUCTION: Patients receive blinatumomab intravenously (IV) continuously over 24 hours on
days 1-28. Treatment repeats every 42 days for 2 courses in the absence of disease
progression or unacceptable toxicity.
RE-INDUCTION: Patients not achieving CR or CRi after Induction, receive blinatumomab IV
continuously over 24 hours on days 1-28 in the absence of disease progression or
POST-REMISSION: Patients receive blinatumomab IV continuously over 24 hours on days 1-28.
Treatment repeats every 42 days for 3 courses in the absence of disease progression or
MAINTENANCE: Patients receive prednisone orally (PO) on days 1-5, vincristine sulfate IV on
day 1, mercaptopurine PO on days 1-28, and methotrexate PO on days 1, 8, 15, and 22.
Treatment repeats every 28 days for 18 courses in the absence of disease progression or
COHORT II (PHILADELPHIA CHROMOSOME POSITIVE PATIENTS):
INDUCTION: Patients receive dasatinib PO twice daily (BID) on days 1-84 and prednisone PO on
days 1-24 with tapering on days 25-32 in the absence of disease progression or unacceptable
RE-INDUCTION: Patients receive blinatumomab IV continuously over 24 hours on days 1-28.
Treatment repeats every 42 days for 2 courses in the absence of disease progression or
POST-REMISSION: Patients receive blinatumomab IV continuously over 24 hours on days 1-28 and
dasatinib PO once daily (QD) on days 1-42. Treatment repeats every 42 days for 3 courses in
the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive dasatinib PO BID on days 1-28 and prednisone PO on days 1-5.
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 2 years,
every 6 months for 2 years, and then annually until 10 years from initial registration.
9L-15-5 A PhII-134, 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
I. To evaluate and compare the progression free survival rate after randomization in the two
treatment arms (nivolumab versus [vs.] observation).
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.
I. To analyze programmed cell death (PD)-ligand (L)1 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
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive nivolumab intravenously (IV) over 60 minutes once every 2 weeks.
Treatment repeats every 2 weeks for 46 courses in the absence of disease progression or
ARM II: Patients undergo standard of care clinical observation for up to 2 years. Upon
disease relapse, patients may cross-over to Arm I.
After completion of study treatment, patients are followed up for 2 years.
9L-11-8: HLA-mismatched allogeneic cellular therapy (HMMACT) after Chemotherapy in High Risk Acute Myeloid Leukemia
There have been no major new drugs for acute leukemia in 30 years. There are approximately 12,000 new cases of Acute myeloid leukemia in the US per year, and allogeneic stem cell transplant may cure 35-50% of these cases.It is believed that HLA-mismatched allogeneic cellular therapy (HMMACT) harnesses a powerful immunologic tool for achieving complete remission in acute leukemias without fewer risks of transplantation or limitations as nearly all patients will have an available donor.The primary objective of this study is to assess the feasibility of cytarabine based chemotherapy and HLA-mismatched allogeneic cellular therapy (HMMACT) in patients with high risk AML, with feasibility measured by induction mortality (IM) and complete response rate.Eligible AML patients will receive induction chemotherapy with mitoxantrone (IV, 3 days) and cytarabine (IV, 7 days) and receive HLA-mismatched G-PBSCs on day 9 or 10. Family donors will concurrently be HLA typed and best available donor will undergo donor screening.This is a Pilot/Feasability study. The primary measures of feasibility will be (1) induction mortality (IM) and (2) complete remission (CR or CRi). Secondary assessments of feasibility will involve safety as measured by the occurrence of serious infections (Grade 4), time to recovery of absolute neutrophil counts and platelets, and incidence of graft versus host disease (GvHD). An additional assessment of feasibility will be the ability to identify a suitable donor in this elderly population. It is expected that between 60% and 80% patients will have a suitable donor; therefore it is anticipated (assuming that only 60% of patients have a donor) that 33-35 patients will be initially recruited to the trial. The number of 20 patients (who actually receive a stem cell infusion) was selected to permit preliminary estimates of toxicities, CRR, EFS and OS. Standard errors (based on 20 patients) for the proportion of patients who experience a CR or IM or GvHD will be 0.11.Follow-up for survival will be done monthly for 3 years or until death. Those no longer followed at our center would be followed by phone call follow-up by the research RN.