Topotecan Hydrochloride and Carboplatin With or Without Veliparib in Treating Advanced Myeloproliferative Disorders and Acute Myeloid Leukemia or Chronic Myelomonocytic Leukemia
NCI 10147: A Phase II Randomized Study of Topotecan/Carboplatin With or Without Veliparib in Advanced Myeloproliferative Disorders and Chronic Myelomonocytic Leukemia (CMML)
Study Overview
Status
Status
Conditions
Conditions
- Acute Myeloid Leukemia
- Polycythemia Vera
- Essential Thrombocythemia
- Myelofibrosis
- Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
- Chronic Myelomonocytic Leukemia
- Recurrent Acute Myeloid Leukemia
- Refractory Acute Myeloid Leukemia
- Myelodysplastic/Myeloproliferative Neoplasm
- Atypical Chronic Myeloid Leukemia
Intervention / Treatment
Intervention / Treatment
Detailed Description
PRIMARY OBJECTIVE:
I. To estimate and compare the complete response/complete response with incomplete recovery (CR/CRi) rate of induction therapy with topotecan hydrochloride (topotecan)/carboplatin (T/C) with or without veliparib (V) in myeloproliferative disorder associated leukemias and chronic myelomonocytic leukemia (CMML).
SECONDARY OBJECTIVES:
I. To evaluate and compare the toxicities of T/C/V versus (vs.) T/C. II. To compare the 2-year disease-free survival (DFS) and overall survival (OS) in response to T/C/V vs. T/C.
III. To detect and compare the presence of minimal residual disease (MRD) remaining after T/C/V vs. T/C.
IV. Evaluate predictive biomarkers of response via assessment of pretreatment impaired homologous recombination via assessment of:
IVa. Next generation sequencing (NGS) panel for genes mutated in myeloid malignancies done as standard of care per institution.
IVb. Functional impairment of deoxyribonucleic acid (DNA) damage response via assessment of pretreatment samples for radiation-induced RAD51 foci.
IVc. Topotecan-induced stabilization of topoisomerase I-DNA covalent complexes, which has recently been observed to be a critical predictor of response to combination of a topoisomerase I poison and PARP inhibitor in xenografts.
V. To evaluate veliparib exposure and contribution to response (efficacy and toxicity).
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive veliparib orally (PO) twice daily (BID) on days 1-21 and topotecan hydrochloride intravenously (IV) continuously over 24 hours and carboplatin IV continuously over 24 hours on days 3-7. Treatment repeats every 28-63 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive topotecan hydrochloride IV continuously over 24 hours and carboplatin IV continuously over 24 hours on days 1-5. Treatment repeats every 28-63 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for a minimum of 30 days, or longer.
Study Type
Study Type
Enrollment (Actual)
Enrollment
Phase
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
California
-
Los Angeles, California, United States, 90033
- USC / Norris Comprehensive Cancer Center
-
Los Angeles, California, United States, 90033
- Los Angeles General Medical Center
-
Newport Beach, California, United States, 92663
- USC Norris Oncology/Hematology-Newport Beach
-
-
Maryland
-
Baltimore, Maryland, United States, 21287
- Johns Hopkins University/Sidney Kimmel Cancer Center
-
-
New Jersey
-
New Brunswick, New Jersey, United States, 08903
- Rutgers Cancer Institute of New Jersey
-
-
North Carolina
-
Chapel Hill, North Carolina, United States, 27599
- UNC Lineberger Comprehensive Cancer Center
-
-
Participation Criteria
Eligibility Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- PRE-REGISTRATION ELIGIBILITY CRITERIA
- Newly diagnosed acute myeloid leukemia (AML) associated with antecedent myeloproliferative disorder (polycythemia vera, essential thrombocythemia, myelofibrosis, atypical chronic myeloid leukemia, chronic myelomonocytic leukemia and related undifferentiated myeloproliferative/myelodysplastic disorders)
- Relapsed/refractory AML associated with antecedent myeloproliferative disorder (polycythemia vera, essential thrombocythemia, myelofibrosis, atypical chronic myeloid leukemia, chronic myelomonocytic leukemia and related undifferentiated myeloproliferative/myelodysplastic disorders) who have received two or fewer prior induction chemotherapy courses
Accelerated phase myeloproliferative disorders per Zeider et al with two or fewer prior therapies
- For aggressive phase myeloproliferative disorders (MPD) (polycythemia vera, essential thrombocythemia, Philadelphia [Ph]-negative chronic myelogenous leukemia), one or more of the following criteria must be met: marrow blasts > 5%, peripheral blood blasts plus progranulocytes > 10%, new onset or increasing myelofibrosis, new onset or > 25% increase in hepatomegaly or splenomegaly, new onset constitutional symptoms (fever, weight loss, splenic pain, bone pain). Zeider et al
- For chronic myelomonocytic leukemia (CMML), the following criteria must be met: 5-19% bone marrow blasts (aggressive) or >= 20% marrow blasts (transformation)
- Bone marrow and/or peripheral blood specimens will be submitted for correlative studies; patients with a dry tap will still be eligible
- RANDOMIZATION ELIGIBILITY CRITERIA
- Bone marrow aspirate and/or peripheral blood specimens were submitted to the central lab and site has confirmation by the local institution that the patient meets one of the criteria specified above
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 or Karnofsky >= 60%
- Total bilirubin less than 2.0 mg/dL unless due to Gilbert's syndrome, then less than 5.0 mg/dL
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) less than 5 x institutional upper limit of normal
- Creatinine clearance glomerular filtration rate (GFR) greater than 30 ml/min per modified Cockcroft-Gault formula
- Interval of greater than 4 weeks since allogeneic blood or marrow transplantation (BMT) if performed; and absence of active graft versus host disease (GVHD)
- The effects of veliparib on the developing human fetus are unknown; for this reason and because PARP inhibiting agents as well as topoisomerase inhibitors and platinating agents are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 months following the last dose of study drug; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of veliparib administration
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study with the exception of hydroxyurea for cytoreduction; therapy with tyrosine kinase inhibitors (TKIs) directed against JAK2, BCR-ABL or FLT3 will be allowed to be continued until 24 hours prior to start of therapy on trial
- Patients with active uncontrolled infection; antibiotic therapy for fevers, and continuation of treatment of prior infection are allowed
- Patients who have active central nervous system (CNS) disease are excluded; patients with known active CNS leukemia should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
- Patients who are receiving any other investigational agents; patients who have completed therapy with an investigational agent should be off this therapy for at least 5 half-lives or two weeks, whichever is shorter
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to veliparib, topotecan or carboplatin
- Uncontrolled intercurrent illness including, but not limited to, active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Pregnant women are excluded from this study because veliparib is PARP inhibiting agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with veliparib, breastfeeding should be discontinued if the mother is treated with veliparib; these potential risks may also apply to topotecan and carboplatin used in this study
- Human immunodeficiency virus (HIV)-patients positive patients are not excluded if they have CD4+ cells >= 250/mm^3 and negligible viral load and are on a stable combination antiretroviral therapy
- History of uncontrolled seizure disorder, including focal or generalized seizure within the past year
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Number of Arms
Arms and Interventions
Participant Group / ArmParticipant Group / Arm |
Intervention / TreatmentIntervention / Treatment |
|---|---|
|
Experimental: Arm A (veliparib, topotecan hydrochloride, carboplatin)
Patients receive veliparib PO BID on days 1-21 and topotecan hydrochloride IV continuously over 24 hours and carboplatin IV continuously over 24 hours on days 3-7.
Treatment repeats every 28-63 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
|
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Given PO
Other Names:
|
|
Active Comparator: Arm B (topotecan hydrochloride, carboplatin)
Patients receive topotecan hydrochloride IV continuously over 24 hours and carboplatin IV continuously over 24 hours on days 1-5.
Treatment repeats every 28-63 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
|
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Number of Participants With a Response
Time Frame: Up to 7 months
|
Based on published standards for acute leukemias, Complete Response (CR) means less than 5% leukemic blasts in the bone marrow, no blasts in the blood, no longer presence of cytogenetic abnormalities, no longer presence of extramedullary disease, with or without absolute neutrophil count or platelet count recovery; Partial Remission (PR) includes the criteria for Complete Remission except there are 5-25% leukemic blasts in the bone marrow and there is absolute neutrophil count and platelet count recovery; Hematologic Improvement (HI) means the disease has not gotten worse and there is at least a 20% decrease in the leukemic blasts in the bone marrow and/or a decrease in leukemia symptoms.
Response = CR, PR, or HI.
|
Up to 7 months
|
Secondary Outcome Measures
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
The Highest Grade Adverse Event Experienced
Time Frame: Up to 7 months
|
Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
|
Up to 7 months
|
|
Number of Participants Without Disease at Study Completion
Time Frame: Up to 7 months
|
Study completion was either death or completion of all protocol-specified activities, whichever came first.
Participants who came off study due to disease-related death were counted as having disease.
|
Up to 7 months
|
|
Duration of Disease-free Survival
Time Frame: Up to 7 months
|
Disease-free survival is defined as participants who are still alive and without disease at study completion.
Study completion was either death or completion of all protocol-specified activities, whichever came first.
|
Up to 7 months
|
|
Number of Participants Still Alive at Study Completion
Time Frame: Up to 7 months
|
Study completion was either death or completion of all protocol-specified activities, whichever came first.
|
Up to 7 months
|
|
Duration of Overall Survival at the Time of Study Completion
Time Frame: Up to 7 months
|
Study completion was either death or completion of all protocol-specified activities, whichever came first.
Duration was measured from the date of registration to the participant's study completion date.
|
Up to 7 months
|
|
Number of Participants With Minimal Residual Disease (MRD) After Treatment
Time Frame: Up to 7 months
|
Minimal residual disease (MRD) refers to a small number of leukemic cells that remain after treatment.
|
Up to 7 months
|
|
Distribution of Mutations in Deoxyribonucleic Acid (DNA) Repair Defects Via Assessment in Leukemia Mutation Panel
Time Frame: Baseline
|
Will be summarized using descriptive statistics.
The association response will be described with appropriate tests for continuously measured biomarkers (t tests, Wilcoxon rank sum tests) and categorical biomarkers (Fisher's exact test).
Descriptive analyses will be performed for the whole cohort and also separately for Arms A and B. Differential treatment outcomes for patient subgroups may be explored using appropriate tests for interactions.
|
Baseline
|
|
Frequency of Patients With Functional Impairment of DNA Damage Response Via Assessment With RAD51 Assay
Time Frame: Baseline
|
Will be reported with exact binomial 95% confidence intervals.
The association response will be described with appropriate tests for continuously measured biomarkers (t tests, Wilcoxon rank sum tests) and categorical biomarkers (Fisher's exact test).
Descriptive analyses will be performed for the whole cohort and also separately for Arms A and B. Differential treatment outcomes for patient subgroups may be explored using appropriate tests for interactions.
|
Baseline
|
|
Topotecan-induced Stabilization of Topoisomerase I-DNA Covalent Complexes
Time Frame: Up to 7 months
|
Topotecan-induced stabilization of topoisomerase I-DNA covalent complexes from peripheral blood
|
Up to 7 months
|
|
Pharmacokinetic Sampling Studies Measured Using a Validated Liquid Chromatography/Tandem Mass Spectrometric Method in Plasma and Bone Marrow
Time Frame: Pre-treatment, day 1, day 8, day 14, day 15, and day 22 (approximately 24 hours post last dose)
|
Plasma trough levels will be obtained weekly through the first cycle to provide a steady-state assessment.
Steady-state plasma concentrations will be calculated for each patient.
Exploratory correlative studies between veliparib exposure (plasma and bone marrow) with pharmacodynamic (biological endpoints, toxicity and efficacy) will be analyzed using nonparametric statistics.
Significance for comparisons will be at the p < 0.05 level.
|
Pre-treatment, day 1, day 8, day 14, day 15, and day 22 (approximately 24 hours post last dose)
|
Collaborators and Investigators
Sponsor
Sponsor
Investigators
Investigators
- Principal Investigator: Keith W Pratz, JHU Sidney Kimmel Comprehensive Cancer Center LAO
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Study Start
Primary Completion (Actual)
Primary Completion
Study Completion (Estimated)
Study Completion
Study Registration Dates
First Submitted
First Submitted
First Submitted That Met QC Criteria
First Submitted That Met QC Criteria
First Posted (Actual)
First Posted
Study Record Updates
Last Update Posted (Actual)
Last Update Posted
Last Update Submitted That Met QC Criteria
Last Update Submitted That Met QC Criteria
Last Verified
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Neoplasms by Site
- Neoplasms
- Chronic Disease
- Disease Attributes
- Neoplasms by Histologic Type
- Hematologic Diseases
- Blood Coagulation Disorders
- Leukemia, Myeloid
- Bone Marrow Diseases
- Hemorrhagic Disorders
- Leukemia
- Blood Platelet Disorders
- Myeloproliferative Disorders
- Bone Marrow Neoplasms
- Hematologic Neoplasms
- Pathological Conditions, Signs and Symptoms
- Hemic and Lymphatic Diseases
- Thrombocytosis
- Leukemia, Myeloid, Acute
- Leukemia, Myelomonocytic, Chronic
- Myelodysplastic-Myeloproliferative Diseases
- Thrombocythemia, Essential
- Polycythemia Vera
- Primary Myelofibrosis
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
- Organic Chemicals
- Heterocyclic Compounds
- Camptothecin
- Alkaloids
- Coordination Complexes
- Carboplatin
- Topotecan
- veliparib
Other Study ID Numbers
Other Study ID Numbers
- NCI-2017-01715 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
- UM1CA186691 (U.S. NIH Grant/Contract)
- ETCTN10147
- 10147 (Other Identifier: CTEP)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Acute Myeloid Leukemia
-
NCT02323607CompletedRecurrent Adult Acute Myeloid Leukemia | Secondary Acute Myeloid Leukemia | Untreated Adult Acute Myeloid Leukemia | Therapy-Related Acute Myeloid Leukemia
-
NCT04354025WithdrawnRefractory Acute Myeloid Leukemia | Relapsed Acute Myeloid Leukemia
-
NCT02109627TerminatedAcute Myeloid Leukemia | Refractory Acute Myeloid Leukemia | Relapsed Acute Myeloid Leukemia
-
NCT02255162TerminatedAcute Myelogenous Leukemia | Acute Myeloid Leukemia (AML) | Acute Myelocytic Leukemia | Acute Granulocytic Leukemia | Acute Non-Lymphocytic Leukemia
-
NCT05488132RecruitingAcute Myeloid Leukemia, in Relapse | Acute Myeloid Leukemia Refractory
-
NCT02944162UnknownAcute Myeloid Leukemia | Acute Myelogenous Leukemia | Acute Myeloid Leukemia With Maturation | Acute Myeloid Leukemia Without Maturation | ANLL
-
NCT01961765CompletedRefractory Acute Myeloid Leukemia | Relapsed Acute Myeloid Leukemia
-
NCT04946890Not yet recruitingAcute Myeloid Leukemia Leukemia
-
NCT04051996Terminated
-
NCT03125239CompletedCombination Merestinib and LY2874455 for Patients With Relapsed or Refractory Acute Myeloid LeukemiaRelapsed Adult Acute Myeloid Leukemia | Refractory Adult Acute Myeloid Leukemia
Clinical Trials on Carboplatin
-
NCT00268905Completed
-
NCT00098878CompletedOvarian Cancer | Fallopian Tube Cancer | Primary Peritoneal Cavity Cancer
-
NCT00002749CompletedBrain and Central Nervous System Tumors
-
NCT00877253Completed
-
NCT07493980Not yet recruiting
-
NCT07285941Recruiting
-
NCT07353723Recruiting
-
NCT06574763Not yet recruiting
-
NCT01445418CompletedBreast Cancer | Ovarian Cancer
-
NCT07103447Not yet recruiting