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Acute Myeloid LeukemiaPhase 2NCT03289910

Topotecan Hydrochloride and Carboplatin With or Without Veliparib in Treating Advanced Myeloproliferative Disorders and Acute Myeloid Leukemia or Chronic Myelomonocytic Leukemia

A Phase 2 study testing Carboplatin, Topotecan and Topotecan Hydrochloride in people with Acute Myeloid Leukemia and Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome, run by National Cancer Institute (NCI) at 6 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record

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Trial summary

This phase II trial studies how well topotecan hydrochloride and carboplatin with or without veliparib work in treating patients with myeloproliferative disorders that have spread to other places in the body and usually cannot be cured or controlled with treatment (advanced), and acute myeloid leukemia or chronic… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Carboplatin, Topotecan and Topotecan Hydrochloride
Could I receive a placebo?
No, everyone receives an active treatment
How many people
25 participants
Where
6 sitesUnited States
Study dates
24 Sep 2018to 18 Dec 2026
Phase
Phase 2

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)
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  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

United States6 sites

  • Johns Hopkins University/Sidney Kimmel Cancer Center

    Baltimore, Maryland, 21287

  • UNC Lineberger Comprehensive Cancer Center

    Chapel Hill, North Carolina, 27599

  • Los Angeles General Medical Center

    Los Angeles, California, 90033

  • USC / Norris Comprehensive Cancer Center

    Los Angeles, California, 90033

  • Rutgers Cancer Institute of New Jersey

    New Brunswick, New Jersey, 08903

  • USC Norris Oncology/Hematology-Newport Beach

    Newport Beach, California, 92663

Other trials in United States

About this study

Official title: NCI 10147: A Phase II Randomized Study of Topotecan/Carboplatin With or Without Veliparib in Advanced Myeloproliferative Disorders and Chronic Myelomonocytic Leukemia (CMML)

This phase II trial studies how well topotecan hydrochloride and carboplatin with or without veliparib work in treating patients with myeloproliferative disorders that have spread to other places in the body and usually cannot be cured or controlled with treatment (advanced), and acute myeloid leukemia or chronic myelomonocytic leukemia. Drugs used in chemotherapy, such as topotecan hydrochloride and carboplatin, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Veliparib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving topotecan hydrochloride, carboplatin, and veliparib may work better in treating patients with myeloproliferative disorders and acute myeloid leukemia or chronic myelomonocytic leukemia compared to topotecan hydrochloride and carboplatin alone.

Read the detailed description

PRIMARY OBJECTIVE:

  1. 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:

  1. 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.

  1. 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.

Being tested
Carboplatin, Topotecan, Topotecan Hydrochloride, Veliparib
Medical subject headings
Leukemia, Myeloid, Acute, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative, Leukemia, Myelomonocytic, Chronic, Thrombocythemia, Essential, Myelodysplastic-Myeloproliferative Diseases, Primary Myelofibrosis, Polycythemia Vera

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CarboplatinDrug

    Also called Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino

    Given IV

  • TopotecanDrug

    Also called Hycamptamine, Topotecan Lactone

    Given IV

  • Topotecan HydrochlorideDrug

    Also called Evotopin, Hycamptamine, Hycamtin, Nogitecan Hydrochloride

    Given IV

  • VeliparibDrug

    Also called ABT 888, ABT-888, ABT888, PARP-1 inhibitor ABT-888

    Given PO

Study groups in NCT03289910
Study groupRoleWhat they receive
Arm A (veliparib, topotecan hydrochloride, carboplatin)ExperimentalPatients 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.
Receives: Drug: Carboplatin; Drug: Topotecan; Drug: Topotecan Hydrochloride; Drug: Veliparib
Arm B (topotecan hydrochloride, carboplatin)Active comparatorPatients 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.
Receives: Drug: Carboplatin; Drug: Topotecan; Drug: Topotecan Hydrochloride

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants With a Response

    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.

    Measured: Up to 7 months

Secondary outcomes (10)

  1. The Highest Grade Adverse Event Experienced

    Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

    Measured: Up to 7 months

  2. Number of Participants Without Disease at Study Completion

    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.

    Measured: Up to 7 months

  3. Duration of Disease-free Survival

    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.

    Measured: Up to 7 months

  4. Number of Participants Still Alive at Study Completion

    Study completion was either death or completion of all protocol-specified activities, whichever came first.

    Measured: Up to 7 months

  5. Duration of Overall Survival at the Time of Study Completion

    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.

    Measured: Up to 7 months

  6. Number of Participants With Minimal Residual Disease (MRD) After Treatment

    Minimal residual disease (MRD) refers to a small number of leukemic cells that remain after treatment.

    Measured: Up to 7 months

  7. Distribution of Mutations in Deoxyribonucleic Acid (DNA) Repair Defects Via Assessment in Leukemia Mutation Panel

    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.

    Measured: Baseline

  8. Frequency of Patients With Functional Impairment of DNA Damage Response Via Assessment With RAD51 Assay

    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.

    Measured: Baseline

  9. Topotecan-induced Stabilization of Topoisomerase I-DNA Covalent Complexes

    Topotecan-induced stabilization of topoisomerase I-DNA covalent complexes from peripheral blood

    Measured: Up to 7 months

  10. Pharmacokinetic Sampling Studies Measured Using a Validated Liquid Chromatography/Tandem Mass Spectrometric Method in Plasma and Bone Marrow

    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.

    Measured: Pre-treatment, day 1, day 8, day 14, day 15, and day 22 (approximately 24 hours post last dose)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Sep 2017
  2. Study start24 Sep 2018
  3. Primary completion31 May 2023
  4. Study completion18 Dec 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Participant
Enrolment
25 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03289910
Sponsor's protocol ID
NCI-2017-01715
Other IDs
NCI-2017-01715, ETCTN10147, 10147, 10147, UM1CA186691
Status last verified
Jun 2026
First submitted
20 Sep 2017
Last updated
23 Jun 2026
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Richardson DR, Green SD, Foster MC, Zeidner JF. Secondary AML Emerging After Therapy with Hypomethylating Agents: Outcomes, Prognostic Factors, and Treatment Options. Curr Hematol Malig Rep. 2021 Feb;16(1):97-111. doi: 10.1007/s11899-021-00608-6. Epub 2021 Feb 20.

    PubMed 33609248

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