Clinical Trials /

Randomized Trial of Topotecan With M6620, an ATR Kinase Inhibitor, in Small Cell Lung Cancers and Small Cell Cancers Outside of the Lungs

NCT03896503

Description:

This phase II trial studies how well M6620 works when given in combination with topotecan hydrochloride (topotecan) compared with topotecan alone in treating patients with small cell lung cancer that has come back (relapsed), or small cell cancer that arises from a site other than the lung (extrapulmonary). Drugs used in chemotherapy, such as topotecan hydrochloride, work by damaging the DNA (deoxyribonucleic acid) in tumor cells, causing those cells to die and the tumor to shrink. However, some tumor cells can become less affected by chemotherapy because they have ways to repair the damaged DNA. The addition of M6620 could help topotecan hydrochloride shrink the cancer and prevent it from returning by blocking enzymes needed for DNA repair.

Related Conditions:
  • Small Cell Carcinoma
  • Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Topotecan With or Without M6620 in Treating Patients With Relapsed Small Cell Lung Cancer or Extrapulmonary Small Cell Cancer
  • Official Title: Randomized Phase II Trial of Topotecan Plus M6620 (VX-970) vs. Topotecan Alone in Patients With Relapsed Small-Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-01769
  • SECONDARY ID: NCI-2019-01769
  • SECONDARY ID: 10268
  • SECONDARY ID: 10268
  • SECONDARY ID: ZIABC011078
  • NCT ID: NCT03896503
  • NCT ALIAS: NCT04162041

Conditions

  • Bladder Small Cell Carcinoma
  • Extensive Stage Lung Small Cell Carcinoma
  • Extrapulmonary Small Cell Carcinoma
  • Limited Stage Lung Small Cell Carcinoma
  • Platinum-Resistant Lung Small Cell Carcinoma
  • Platinum-Sensitive Lung Small Cell Carcinoma
  • Prostate Small Cell Carcinoma
  • Recurrent Lung Small Cell Carcinoma

Interventions

DrugSynonymsArms
ATR Kinase Inhibitor M6620M 6620, M6620, VX-970Arm II (topotecan hydrochloride, ATR kinase inhibitor M6620)
TopotecanHycamptamine, Topotecan LactoneArm I (topotecan hydrochloride )
Topotecan HydrochlorideHycamptamine, Hycamtin, SKF S-104864-A, Topotecan HCl, topotecan hydrochloride (oral)Arm I (topotecan hydrochloride )

Purpose

This phase II trial studies how well M6620 works when given in combination with topotecan hydrochloride (topotecan) compared with topotecan alone in treating patients with small cell lung cancer that has come back (relapsed), or small cell cancer that arises from a site other than the lung (extrapulmonary). Drugs used in chemotherapy, such as topotecan hydrochloride, work by damaging the DNA (deoxyribonucleic acid) in tumor cells, causing those cells to die and the tumor to shrink. However, some tumor cells can become less affected by chemotherapy because they have ways to repair the damaged DNA. The addition of M6620 could help topotecan hydrochloride shrink the cancer and prevent it from returning by blocking enzymes needed for DNA repair.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine if the combination of ATR kinase inhibitor M6620 (M6620) with topotecan
      hydrochloride (topotecan) will result in an improvement in progression-free survival (PFS)
      compared to topotecan alone in patients with relapsed small cell lung cancer (SCLC).

      SECONDARY OBJECTIVE:

      I. To determine the objective response rate (ORR) and overall survival (OS) with the
      combination of M6220 and topotecan in patients with relapsed SCLC and extrapulmonary small
      cell cancers.

      EXPLORATORY OBJECTIVES:

      I. To perform molecular profiling assays on malignant and normal tissues, including, but not
      limited to ribonucleic acid (RNA) sequencing (RNA-Seq):

      Ia. To assess expression of genes Schlafen family member 11 (SLFN11), MYC, and
      ataxia-telangiesctasia mutated (ATM) among others.

      Ib. To identify potential predictive biomarkers of response to a combination of M6620 with
      topotecan.

      Ic. Identify mechanisms of drug sensitivity and resistance using deoxyribonucleic acid (DNA)-
      and RNA-based assessment platforms.

      II. To contribute genetic analysis data from de-identified biospecimens to Genomic Data
      Commons (GDC), a well annotated cancer molecular and clinical data repository, for current
      and future research; specimens will be annotated with key clinical data, including
      presentation, diagnosis, staging, summary treatment, and if possible, outcome.

      III. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA
      analysis), and nucleic acids obtained from patients at the Experimental Therapeutics Clinical
      Trial Network (ETCTN) Biorepository at Nationwide Children's Hospital.

      IV. To characterize circulating cell-free DNA (cfDNA) and circulating tumor cells in patients
      with relapsed SCLC and extrapulmonary small cell cancers.

      V. To identify potential predictive biomarkers of response to a combination of M6620 with
      topotecan in patients with extrapulmonary small cell cancers.

      OUTLINE: Patients are randomized to 1 of 2 arms. Patients with extrapulmonary small cell
      cancer are assigned to Arm II while patients with relapsed small cell lung cancer are
      assigned to both arms.

      ARM I: Patients receive topotecan hydrochloride intravenously (IV) over 30 minutes on days
      1-5. Cycles repeat every 21 days in the absence of disease progression or unacceptable
      toxicity. Patients may crossover to Arm II at disease progression.

      ARM II: Patients receive topotecan hydrochloride IV over 30 minutes on days 1-5 and M6620 IV
      over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 4 weeks and then every 3
      months.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (topotecan hydrochloride )Active ComparatorPatients receive topotecan hydrochloride IV over 30 minutes on days 1-5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may crossover to Arm II at disease progression.
  • Topotecan
  • Topotecan Hydrochloride
Arm II (topotecan hydrochloride, ATR kinase inhibitor M6620)ExperimentalPatients receive topotecan hydrochloride IV over 30 minutes on days 1-5 and ATR kinase inhibitor M6620 IV over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • ATR Kinase Inhibitor M6620
  • Topotecan
  • Topotecan Hydrochloride

Eligibility Criteria

        Inclusion Criteria:

          -  Patients enrolled to the primary cohort must have limited- or extensive-disease SCLC
             at diagnosis, with relapse at study entry with measurable disease at random assignment
             per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Both platinum-sensitive
             and platinum-resistant patients will be included

          -  Patients with extrapulmonary small cell cancers (cancers with small cell morphology
             and arising outside the lung, such as small cell prostate, bladder, etc) will be
             eligible for the exploratory cohort

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Hemoglobin >= 9.0 g/dL - patients may receive transfusion to meet the hemoglobin (Hb)
             eligibility

          -  Absolute neutrophil count (ANC) >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  Total bilirubin =< 2 mg/dL

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 3.0 x institutional upper limit of normal (ULN)

          -  Creatinine =< institutional ULN OR

          -  Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 unless data exists supporting
             safe use at lower kidney function values, no lower than 30 mL/min/1.73m^2

          -  Human immunodeficiency virus (HIV)-positive subjects on combination antiretroviral
             therapy are eligible as long as they are on effective anti-retroviral therapy with
             undetectable viral load within 6 months and there is no drug-drug interaction with
             M6220

          -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
             load must be undetectable on suppressive therapy, if indicated

          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated
             and cured. For patients with HCV infection who are currently on treatment, they are
             eligible if they have an undetectable HCV viral load

          -  The effects of M6620 on the developing human fetus are unknown. For this reason and
             because DNA-damage response (DDR) inhibitors as well as other therapeutic agents used
             in this trial 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 after completion of M6620 administration. 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 for 6 months after completion of M6620
             administration

          -  Patients with treated brain metastases are eligible if they are symptomatically stable
             while off steroid therapy for a minimum of 21 days

          -  Patients with a prior or concurrent malignancy whose natural history or treatment does
             not have the potential to interfere with the safety or efficacy assessment of the
             investigational regimen are eligible for this trial

          -  Patients with known history or current symptoms of cardiac disease, or history of
             treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
             function using the New York Heart Association Functional Classification. To be
             eligible for this trial, patients should be class 2B or better

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Patients with symptomatic brain metastasis are not eligible due to their extremely
             poor prognosis and since it is unclear whether the investigational agent penetrates
             the blood-brain barrier. However, subjects who have had treatment for their brain
             metastasis and are symptomatically stable while off steroid therapy for a minimum of
             21 days may be enrolled

          -  Patients who have received prior topotecan therapy

          -  Patients who have had chemotherapy or radiotherapy within 3 weeks prior to enrollment

          -  Patients who have not recovered from adverse events due to prior anti-cancer therapy
             except hair loss and peripheral neuropathy (i.e., have residual toxicities > grade 1)

          -  Patients who are receiving any other investigational agents

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to M6620 or topotecan used in study

          -  M6620 is primarily metabolized by CYP3A4; therefore, concomitant administration with
             strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin,
             ritonavir, indinavir, nelfinavir and saquinavir) or inducers of CYP3A4 (e.g.,
             rifampin, phenytoin, carbamazepine, phenobarbital, St. John's wort) should be avoided.
             Patients requiring any medications or substances that are strong inhibitors or
             inducers of CYP3A during the course of the study are ineligible. Because the lists of
             these agents are constantly changing, it is important to regularly consult a
             frequently-updated medical reference for a list of drugs to avoid or of which to
             minimize use. The Patient Drug Interactions Handout and Wallet Card should be provided
             to patients. As part of the enrollment/informed consent procedures, the patient will
             be counseled on the risk of interactions with other agents, and what to do if new
             medications need to be prescribed or if the patient is considering a new
             over-the-counter medicine or herbal product

          -  Patients with uncontrolled intercurrent illness

          -  Pregnant women are excluded from this study because M6620 as a DDR inhibitor may have
             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 M6620, breastfeeding should be discontinued if the mother is treated with
             M6620. These potential risks may also apply to topotecan used in this study

          -  Patients with high grade neuroendocrine cancers, but with no small cell morphology
             will not be eligible

          -  Patients with psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Patients with Li-Fraumeni syndrome will not be eligible
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:From start of treatment to time of progression or death, whichever occurs first, assessed at 6 months after last patient has enrolled
Safety Issue:
Description:The combination of M6620 with topotecan will be compared to topotecan alone in patients with relapsed small cell lung cancer (SCLC). Kaplan-Meier curves and a one-tailed log-rank test will be the primary analysis methods.

Secondary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Overall survival (OS)
Time Frame:Up to 2 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

December 9, 2019