Clinical Trials /

Trial of Topotecan With VX-970 (M6620), an ATR Kinase Inhibitor, in Small Cell Cancers and Extrapulmonary Small Cell Cancers

NCT02487095

Description:

Background: Chemotherapy damages cancer cell DNA so the cells die and the tumor shrinks. But it may stop working in some people over time. This is partly due to efficient DNA damage repair mechanisms used by tumor cells. VX-970 (M6620) may stop cancer cells from preventing the repair of DNA damaged by chemotherapy. The purpose of this study is to see if using the chemotherapy drug topotecan along with the drug VX-970 (M6620) will improve the response to chemotherapy. Objective: To study the safety and efficacy of VX-970 (M6620) and topotecan in treating small cell lung cancer. Eligibility: Adults at least 18 years old with small cell lung cancer . Design: Participants will be screened with medical history, physical exam, blood and heart tests, and scans. Most of these tests are part of their routine care. Most of these tests will be repeated throughout the study. The study is set in 21-day cycles. Participants will get topotecan IV on days 1 through 5. They will get VX-970 (M6620) IV on day 5 alone or on day 5 and day 2. Participants doctors will monitor them weekly for the first cycle, every 3 weeks after that. For Part 1 of this Study the doses of topotecan and VX-970 (M6620) will be increased (according to the Protocol) to determine the maximum safe dose of the combination. The maximum safe dose of the combination is the dose at which no more than 1 in 6 people have an intolerable side effect. More participants will join in Phase 2. They will take the drugs at the maximum safe dose, on the same schedule as the drugs were taken in Phase 1. Participants will give samples of blood, hair, and tumor tissue (optional) at different times. They will discuss side effects at every visit. A month after stopping taking the drugs, participants will have a physical exam and blood drawn. They will have follow-up phone calls every 3 months.

Related Conditions:
  • Cervical Carcinoma
  • Neuroendocrine Carcinoma
  • Non-Small Cell Lung Carcinoma
  • Ovarian Carcinoma
  • Small Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trial of Topotecan With VX-970 (M6620), an ATR Kinase Inhibitor, in Small Cell Cancers and Extrapulmonary Small Cell Cancers
  • Official Title: A Phase I/II Trial of Topotecan With VX-970 (M6620), an ATR Kinase Inhibitor in Small Cell Cancers

Clinical Trial IDs

  • ORG STUDY ID: 150150
  • SECONDARY ID: 15-C-0150
  • NCT ID: NCT02487095

Conditions

  • Carcinoma, Non-Small -Cell Lung
  • Ovarian Neoplasms
  • Small Cell Lung Carcinoma
  • Uterine Cervical Neoplasms
  • Carcinoma, Neuroendocrine
  • Extrapulmonary Small Cell Cancer

Interventions

DrugSynonymsArms
Topotecan2/Phase II
VX-970 (M6620)2/Phase II

Purpose

Background: Chemotherapy damages cancer cell DNA so the cells die and the tumor shrinks. But it may stop working in some people over time. This is partly due to efficient DNA damage repair mechanisms used by tumor cells. VX-970 (M6620) may stop cancer cells from preventing the repair of DNA damaged by chemotherapy. The purpose of this study is to see if using the chemotherapy drug topotecan along with the drug VX-970 (M6620) will improve the response to chemotherapy. Objective: To study the safety and efficacy of VX-970 (M6620) and topotecan in treating small cell lung cancer. Eligibility: Adults at least 18 years old with small cell lung cancer . Design: Participants will be screened with medical history, physical exam, blood and heart tests, and scans. Most of these tests are part of their routine care. Most of these tests will be repeated throughout the study. The study is set in 21-day cycles. Participants will get topotecan IV on days 1 through 5. They will get VX-970 (M6620) IV on day 5 alone or on day 5 and day 2. Participants doctors will monitor them weekly for the first cycle, every 3 weeks after that. For Part 1 of this Study the doses of topotecan and VX-970 (M6620) will be increased (according to the Protocol) to determine the maximum safe dose of the combination. The maximum safe dose of the combination is the dose at which no more than 1 in 6 people have an intolerable side effect. More participants will join in Phase 2. They will take the drugs at the maximum safe dose, on the same schedule as the drugs were taken in Phase 1. Participants will give samples of blood, hair, and tumor tissue (optional) at different times. They will discuss side effects at every visit. A month after stopping taking the drugs, participants will have a physical exam and blood drawn. They will have follow-up phone calls every 3 months.

Detailed Description

      Background:

      Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis.

      Although highly responsive to chemotherapy initially, SCLC typically relapses quickly and
      becomes refractory to treatment within a few months.

      There is only one FDA approved treatment for patients with relapsed SCLC after first-line
      chemotherapy: topotecan, which inhibits religation of topoisomerase I-mediated single-strand
      DNA breaks leading to lethal doublestrand DNA breaks.

      The survival of some SCLC cells despite initial tumor sensitivity to chemotherapy suggests
      the existence of a highly effective DNA damage response network.

      SCLC is characterized by high replication stress (RB1 inactivation, MYC and CCNE1 activation)
      and defective ATM-p53 signaling pathway, which cause an excessive reliance on ATR for
      survival following DNA damage.

      We hypothesize that a combination of ATR kinase inhibition with DNA damaging agents such as
      topotecan will provide an attractive synthetically lethal therapeutic option for SCLC.

      VX-970 is a potent and selective kinase inhibitor of ATR, and in vitro data support the
      hypothesis that ATR inhibition can improve SCLC responses to DNA damaging agents.

      Primary objectives:

      Phase 1: To identify the maximum tolerated dose (MTD) of topotecan in combination with
      VX-970.

      Phase 2: To assess the efficacy with respect to clinical response rate of a combination of
      topotecan and VX-970 in the second-line treatment of patients with SCLC.

      Eligibility:

      Both Phase 1 and 2: Subjects must be greater than or equal to 18 years of age and have a
      performance status (ECOG) less than or equal to 2. Subjects must not have received
      chemotherapy, or undergone major surgery within 4 weeks and radiotherapy within 24 hours
      prior to enrollment.

      Phase 1: Subjects with histologically confirmed SCLC, NSCLC, ovarian cancer, cervical cancer,
      and neuroendocrine cancers, and at least one prior chemotherapy. Patients with other
      histolgies will be allowed if no standard treatment options exist. Patients with evaluable,
      but not measurable disease will be eligible for Phase I.

      Phase 2: Subjects with histological confirmation of SCLC and one prior platinum-based
      chemotherapy. Patients with both platinum-sensitive and platinum-refractory disease will be
      eligible. Patients must have measurable disease to be eligible for Phase II.

      Design:

      Participants meeting inclusion and exclusion criteria will receive topotecan and VX-970
      administered every 21 days (1 cycle), until disease progression or development of intolerable
      side effects.

      Blood and hair samples will be collected at multiple time points during cycle 1
      (pre-treatment on day 1, post treatment on days 2, and 3) for PD analyses.

      Tumor biopsies, which are optional, will be obtained at baseline, during the first treatment
      cycle (approximately 15 hours after the first dose of VX-970 on day 3) and at disease
      progression except for subjects at the first dose level.

      Participants at the first dose level will undergo biopsies on day 3 prior to third dose of
      topotecan.

      Participants will be monitored weekly during the first cycle by clinic visit and basic labs.

      Toxicity will be graded according to CTCAE version 4.0, and tumor assessments will be made
      using CT scans (chest, abdomen and pelvis) at baseline and after every 2 cycles according to
      Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1.

      Follow-up for survival will be carried out every 3 months.
    

Trial Arms

NameTypeDescriptionInterventions
1/Phase IExperimentalVX-970 + (M6620) topotecan at escalating doses
  • Topotecan
  • VX-970 (M6620)
2/Phase IIExperimentalVX-970 + (M6620) topotecan at MTD/RP2D
  • Topotecan
  • VX-970 (M6620)

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Both Phase I and Phase II:

               -  Male and female subjects greater than or equal to 18 years of age. Because no
                  dosing adverse event data are currently available on the use of topotecan in
                  combination with VX-970 (M6620) in subjects less than 18 years of age, children
                  are excluded from this study, but will be eligible for future pediatrics trials.

               -  ECOG performance status less than or equal to 2 (Performance Status Criteria)

               -  Patients must have measurable disease, per RECIST 1.1. Subjects with evaluable,
                  but not measurable disease will be eligible for Phase 1.

               -  Subjects must not have received chemotherapy, or undergone major surgery within 4
                  weeks and radiotherapy within 24 hours prior to enrollment.

               -  Adequate organ functions

                    -  Hemoglobin greater than or equal to 9.0 g/dL

                    -  Absolute neutrophil count greater than or equal to 1.5x10^9/L

                    -  Platelets greater than or equal to 100x10^9/L

                    -  Total Bilirubin less than or equal to 2.0 mg/dL

                    -  Transaminases less than or equal to 2 x ULN or if liver metastases were
                       present, less than or equal to 3xULN

                    -  Creatinine less than or equal to 1.5 mg/dL or creatinine clearance by
                       Cockcroft-Gault formula greater than or equal to 60 mL/min

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

               -  The effects of VX-970 (M6620) on the developing human fetus are unknown For this
                  reason and because topotecan is known to be teratogenic, women of child-bearing
                  potential and men must agree to use adequate contraception (hormonal or barrier
                  method of birth control; abstinence) prior to study entry, during study
                  participation and for 6 months after the last dose study therapy. 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.

          -  Phase I:

               -  Subjects with histologically confirmed SCLC, NSCLC, ovarian cancer, cervical
                  cancer, and neuroendocrine cancers will be eligible. Pathological confirmation of
                  diagnosis will be done at NCI Laboratory of Pathology. Patients with other
                  histologies will be allowed if no standard treatment options exist.

               -  At least one prior chemotherapy

               -  NSCLC subjects with EGFR mutations or ALK translocations should have previously
                  received appropriate FDA approved therapies in addition to prior chemotherapy

          -  Phase II:

               -  Histological confirmation of SCLC, or extrapulmonary small cell cancer. Although
                  NCI confirmation of pathology is not required prior to starting treatment, every
                  effort will be made to obtain outside pathology to be reviewed by an NCI
                  pathologist.

               -  Subjects with both platinum-sensitive and platinum-refractory disease will be
                  eligible

        EXCLUSION CRITERIA:

          -  Subjects with tumor amenable to potentially curative therapy.

          -  Subjects who are receiving any other investigational agents.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to (study agent) or other agents used in study.

          -  Subjects with symptomatic brain metastases will be excluded from trial secondary to
             poor prognosis. However, subjects who have had treatment for their brain metastasis
             and whose brain disease is stable without steroid therapy for 1 week or on physiologic
             doses of steroids may be enrolled.

          -  Subjects requiring any medications or substances that are strong inhibitors or
             inducers of CYP3A during the course of the study are ineligible. Lists including
             strong inhibitors and inducers of CYP 3A4 are provided.

          -  Subjects with evidence of severe or uncontrolled systemic disease, or any concurrent
             condition, which could compromise participation in the study, including, but not
             limited to, active or uncontrolled infection, immune deficiencies, Hepatitis B,
             Hepatitis C, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive
             heart failure, unstable angina pectoris, myocardial infarction within the past 6
             months, uncontrolled cardiac arrhythmia, stroke/cerebrovascular accident within the
             past 6 months, or psychiatric illness/social situations which would jeopardize
             compliance with the protocol.

          -  HIV-positive subjects on combination antiretroviral therapy are ineligible because of
             the potential for pharmacokinetic interactions with VX-970 (M6620). In addition, these
             subjects are at increased risk of lethal infections when treated with
             marrow-suppressive therapy.

          -  Pregnant women are excluded from this study because topotecan is a Class D agent with
             the potential for teratogenic or abortifacient effects and because the effects of
             VX-970 (M6620) on the developing human fetus are currently unknown. In addition,
             because there is an unknown but potential risk for adverse events in nursing infants
             secondary to treatment of the mother with topotecan or VX-970 (M6620), breastfeeding
             should be discontinued if the mother is treated with these agents.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Ph I: Maximum Tolerated Dose (MTD) of topotecan in combination with VX-970 (M6620)
Time Frame:End of Cycle 1
Safety Issue:
Description:MTD will be determined as DLT occurring at the highest dose level

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • RB1 Inactivation
  • Kinase Inhibitor
  • DNA Damage Response Network
  • MYC And CCNE1 Activation
  • Defective ATM-p53 Signaling Pathway

Last Updated

October 18, 2019