Clinical Trials /

M7824 and Topotecan or Temozolomide in Relapsed Small Cell Lung Cancers

NCT03554473

Description:

BACKGROUND: - Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis. Although highly responsive to chemotherapy initially, SCLC relapses quickly and becomes refractory to treatment within a few months. - The inability to destroy residual SCLC cells despite initial chemosensitivity suggests the existence of a highly effective DNA damage response network. SCLC is also characterized by high DNA replication stress (RB1 inactivation, MYC and CCNE1 activation). - 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 double-strand DNA breaks. Temozolomide, an oral alkylating agent, which causes DNA damage by alkylating guanine at position O6 also has activity in relapsed SCLC, particularly for brain metastases. - Preliminary evidence indicates that disruption of the immune checkpoint PD-1/PD-L1 pathway can yield responses in a subset of SCLC patients, but response rates (approximately equal to 10%) are lower than NSCLC and other tumors with comparable tumor mutational burden indicating additional immunosuppressive mechanisms at play in the SCLC tumor microenvironment. - M7824 is a bifunctional fusion protein consisting of an anti-programmed death ligand 1 (PDL1) antibody and the extracellular domain of transforming growth factor beta (TGF-beta) receptor type 2, a TGF-beta trap. - Safety data from the dose-escalation study in solid tumors as well as preliminary data from expansion cohorts show that M7824 has a safety profile similar to other checkpoint inhibiting compounds. - Combining immunotherapy, and chemotherapy could synergistically improve the anticancer activity of immunotherapy. Combination of chemotherapy with immunotherapy have improved outcomes in NSCLC and melanoma leading to FDA approvals of such combinations. - We hypothesize that increased DNA damage induced by topotecan and temozolomide will complement the anti-tumor activity of M7824, in recurrent SCLC. OBJECTIVE: - The primary objective of the trial is to determine the efficacy (using objective response rate) of M7824 plus topotecan or temozolomide in relapsed SCLC. ELIGIBILITY: - Subjects with histological or cytological confirmation of SCLC. - 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 2 weeks and radiotherapy within 24 hours prior to enrollment. - Subjects must have adequate organ function and measurable disease. DESIGN: - Arm A (M7824 monotherapy): Up to 10 patients may be treated with M7824 monotherapy to obtain safety and PK data, and a preliminary estimate of clinical responses to M7824 in SCLC. Patients with progressive disease on Arm A may then receive M7824 plus temozolomide as per description of treatment for Arm C. - Arm B (M7824 plus topotecan) and Arm C (M7824 plus temozolomide) will be administered in 3 and 4-week cycles respectively; these arms will have a safety run-in followed by efficacy analysis. Up to 10 patients with extrapulmonary small cell cancer will be enrolled in arm C to receive the combination of M7824 and temozolomide. - Optional tumor biopsies will be obtained at pre-treatment on C1D1 and C1D15 for Arm C; pre-treatment on C1D1 and C2D1 for arms A and B. - Every subject of each arm of the safety run-in will be observed for at least 7 days after first dose of M7824 before the subsequent subject can be treated. Subjects who are not evaluable for DLT will be replaced and not included into evaluation ARMS: - Arm A (3-week cycles): M7824 monotherapy 2400 mg every 3 weeks until disease progression or a criterion in Protocol is met. Patients with progressive disease on Arm A may then receive 1200 mg M7824 every 2 weeks plus temozolomide 200 mg/m^2/day on days 1-5 every 4 weeks. - Arm B (3-week cycles): M7824 2400 mg plus topotecan 1 mg/m2 on days 1-5 every 3 weeks until disease progression or a criterion in Protocol is met. - Arm C (4-week cycles): M7824 1200 mg every 2 weeks plus temozolomide 200 mg/m2/day on days 1-5 every 4 weeks until disease progression or a criterion in Protocol is met. Dose de-escalation Schedule Arm B Dose Level: M7824 - Topotecan Level 1 2400 mg every 3 weeks - 1 mg/m(2) on days 1-5 every 3 weeks Level-1 2400 mg every 3 weeks - 0.75 mg/m(2) on days 1-5 every weeks Dose de-escalation Schedule Arm C Dose Level: M7824 - Temozolomide Level 1200 mg every 2 weeks - 200 mg/m(2)/day on days 1-5 every 4 weeks Level-1 1200 mg every 2 weeks - 150 mg/m(2) day on days 1-5 every 4 weeks

Related Conditions:
  • Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: M7824 and Topotecan or Temozolomide in Relapsed Small Cell Lung Cancers
  • Official Title: Safety Run-In and Phase II Trial of M7824 and Topotecan or Temozolomide in Relapsed Small Cell Lung Cancers

Clinical Trial IDs

  • ORG STUDY ID: 180110
  • SECONDARY ID: 18-C-0110
  • NCT ID: NCT03554473

Conditions

  • Carcinoma, Small Cell
  • Lung Cancer
  • Small Cell Lung Cancer

Interventions

DrugSynonymsArms
M7824Arm A/M7824 Monotherapy
TopotecanArm B/M7824 plus topotecan
TemozolomideArm C/M7824 plus temozolomide safety

Purpose

Background: Small cell lung cancer (SCLC) is an aggressive cancer. People with SCLC tend to be respond well to chemotherapy at first, but become resistant to treatment after a few months. Researchers want to see if combining two chemotherapy drugs with the drug M7824 will help the immune system fight tumors in people with SCLC. The chemotherapy drugs are topotecan and temolozomide. Objective: To determine the efficacy of M7824 plus topotecan or temozolomide in relapsed SCLC. Eligibility: Adults ages 18 and older diagnosed with SCLC whose disease has not responded to prior treatment Design: Participants will be screened with - Blood and urine tests - Medical history - Physical exam - Electrocardiogram to test heart function - Computed tomography and positron emission tomography scans Participants will be divided into three groups. Group A and Group B will get M7824 through a tube inserted in a vein for about 1 hour on Day 1 of a 21-day cycle. Group B will also get topotecan in a vein for about 30 minutes on Days 1 through 5 Group C will get M7824 for 1 hour on Days 1 and 15 of a 28-day cycle. They will also take temozolomide by mouth for 5 days each cycle. Group A will continue cycles as long as the disease responds to treatment. If it gets worse, they may be moved to Group B or C. During the study, participants will have physical exams and blood tests. They may have tumor samples taken. Participants will have a follow-up visit about 4 weeks after stopping the study drugs. They will have a physical exam and blood will be drawn.

Detailed Description

      BACKGROUND:

        -  Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis. Although
           highly responsive to chemotherapy initially, SCLC relapses quickly and becomes
           refractory to treatment within a few months.

        -  The inability to destroy residual SCLC cells despite initial chemosensitivity suggests
           the existence of a highly effective DNA damage response network. SCLC is also
           characterized by high DNA replication stress (RB1 inactivation, MYC and CCNE1
           activation).

        -  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 double-strand DNA breaks.
           Temozolomide, an oral alkylating agent, which causes DNA damage by alkylating guanine at
           position O6 also has activity in relapsed SCLC, particularly for brain metastases.

        -  Preliminary evidence indicates that disruption of the immune checkpoint PD-1/PD-L1
           pathway can yield responses in a subset of SCLC patients, but response rates
           (approximately equal to 10%) are lower than NSCLC and other tumors with comparable tumor
           mutational burden indicating additional immunosuppressive mechanisms at play in the SCLC
           tumor microenvironment.

        -  M7824 is a bifunctional fusion protein consisting of an anti-programmed death ligand 1
           (PDL1) antibody and the extracellular domain of transforming growth factor beta
           (TGF-beta) receptor type 2, a TGF-beta trap.

        -  Safety data from the dose-escalation study in solid tumors as well as preliminary data
           from expansion cohorts show that M7824 has a safety profile similar to other checkpoint
           inhibiting compounds.

        -  Combining immunotherapy, and chemotherapy could synergistically improve the anticancer
           activity of immunotherapy. Combination of chemotherapy with immunotherapy have improved
           outcomes in NSCLC and melanoma leading to FDA approvals of such combinations.

        -  We hypothesize that increased DNA damage induced by topotecan and temozolomide will
           complement the anti-tumor activity of M7824, in recurrent SCLC.

      OBJECTIVE:

      - The primary objective of the trial is to determine the efficacy (using objective response
      rate) of M7824 plus topotecan or temozolomide in relapsed SCLC.

      ELIGIBILITY:

        -  Subjects with histological or cytological confirmation of SCLC.

        -  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 2 weeks
           and radiotherapy within 24 hours prior to enrollment.

        -  Subjects must have adequate organ function and measurable disease.

      DESIGN:

        -  Arm A (M7824 monotherapy): Up to 10 patients may be treated with M7824 monotherapy (1800
           or 2400 mg every 3 weeks on a 3-week cycle) to obtain safety and PK data, and a
           preliminary estimate of clinical responses to M7824 in SCLC.

        -  Arm B (M7824 plus topotecan) and Arm C (M7824 plus temozolomide) will be administered in
           3 and 4-week cycles respectively; these arms will have a safety run-in followed by
           efficacy analysis.

        -  Optional tumor biopsies will be obtained at pre-treatment on C1D1 and C1D15 for Arm C;
           pre-treatment on C1D1 and C2D1 for arms A and B.

        -  Every subject of each arm of the safety run-in will be observed for at least 7 days
           after first dose of M7824 before the subsequent subject can be treated. Subjects who are
           not evaluable for DLT will be replaced and not included into evaluation

      ARMS:

        -  Arm A (3-week cycles): M7824 monotherapy 1800 or 2400 mg every 3 weeks.

        -  Arm B (3-week cycles): M7824 2400 mg plus topotecan 1 mg/m2 on days 1-5 every 3 weeks.
           After 6 cycles, M7824 will be continued as monotherapy 2400 mg every 3 weeks.

        -  Arm C (4-week cycles): M7824 1200 mg every 2 weeks plus temozolomide 200 mg/m2/day on
           days 1-5 every 4 weeks. After 6 cycles, M7824 will be continued as monotherapy 1200 mg
           every 2 weeks.

      Dose de-escalation Schedule Arm B

      Dose Level: M7824 - Topotecan

      Level 1 2400 mg every 3 weeks - 1 mg/m(2) on days 1-5 every 3 weeks

      Level-1 2400 mg every 3 weeks - 0.75 mg/m(2) on days 1-5 every weeks

      Dose de-escalation Schedule Arm C

      Dose Level: M7824 - Temozolomide

      Level 1200 mg every 2 weeks - 200 mg/m(2)/day on days 1-5 every 4 weeks

      Level-1 1200 mg every 2 weeks - 150 mg/m(2) day on days 1-5 every 4 weeks
    

Trial Arms

NameTypeDescriptionInterventions
Arm A/M7824 MonotherapyExperimentalM7824 (IV) monotherapy once every 21 days on a21-day cycle.
  • M7824
Arm B/M7824 plus topotecanExperimentalM7824 plus topotecan: At least 6 subjects randomizedto receive M7824 plus topotecan to determine safety. 4 more patients enrolled at initial or lower dose forefficacy. If efficacious, an additional 12 subjects enrolled.
  • M7824
  • Topotecan
Arm C/M7824 plus temozolomide safetyExperimentalM7824 plus temozolomide: At least 6 subjects randomized to receive M7824 plus temozolomide todetermine safety. 4 more patients enrolled at initial orlower dose for efficacy. If efficacious, an additional 12 subjects enrolled.
  • M7824
  • Temozolomide

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Patients must have must have histologically or cytologically confirmed SCLC.

          -  Subjects who progressed on at least one prior chemotherapy.

          -  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, temozolomide and
             M7824 in subjects 18 years of age, children are excluded from this study.

          -  ECOG performance status greater than or equal to 2.

          -  Subjects must have measurable disease per RECIST 1.1

          -  Subjects must not have received chemotherapy, or undergone major surgery within 2
             weeks and radiotherapy within 24 hours prior to enrollment.

          -  Patients must have adequate organ and marrow function as defined below:

               -  hemoglobin greater than or equal to 9.0 g/dL

               -  absolute neutrophil count greater than or equal to 1.5x109/L

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

               -  total bilirubin less than or equal to 2.0 mg/dL

               -  AST (SGOT)/ALT(SGPT) less than or equal to 2.5 x ULN or if liver metastases were
                  present, less than or equal to 5 x ULN

               -  creatinine less than or equal to 1.5 mg/dL

        OR

        --creatinine clearance greater than or equal to 40 mL/min

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

          -  The effects of the trial treatment on the developing human fetus are unknown; thus,
             women of childbearing potential and men must agree to use highly-effective
             contraception prior to study entry, for the duration of study participation and up to
             120 days after the last dose of the 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.

        EXCLUSION CRITERIA:

          -  Subjects with tumor amenable to potentially curative therapy per PI.

          -  Subjects who are receiving any other investigational agents. Prior immunotherapy,
             topotecan and temozolomide are allowed.

          -  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 asymptomatic brain metastases, and those
             had treatment for their brain metastasis and whose brain disease is stable without
             steroid therapy for 2 weeks may be enrolled (replacement doses less than or equal to
             10 mg of prednisone or equivalent per day are allowed).

          -  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 (HIV-positive
             subjects on combination antiretroviral therapy are eligible), Hepatitis B, Hepatitis
             C, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart
             failure, unstable angina pectoris, myocardial infarction within the past 3 months,
             uncontrolled cardiac arrhythmia, stroke/cerebrovascular accident within the past 3
             months, bleeding diathesis or recent (within 3 months) clinically significant bleeding
             events or psychiatric illness/social situations which would jeopardize compliance with
             the protocol.

          -  Pregnant women are excluded from this study because topotecan and temozolomide are
             Class D agents with the potential for teratogenic or abortifacient effects and because
             the effects of M7824 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, temozolomide or M7824,
             breastfeeding should be discontinued if the mother is treated with these agents

          -  Active autoimmune disease that might deteriorate when receiving an immunostimulatory
             agent with the exceptions:

               -  Diabetes type I, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not
                  requiring immunosuppressive treatment are eligible;

               -  Subjects requiring hormone replacement with corticosteroids are eligible if the
                  steroids are administered only for the purpose of hormonal replacement and at
                  doses less than or equal to 10 mg of prednisone or equivalent per day;

               -  Administration of steroids for other conditions through a route known to result
                  in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation)
                  is acceptable.

          -  Systemic therapy with immunosuppressive agents within 7 days before enrollment.

          -  Administration of live vaccines within 21 days prior to enrollment.

          -  Known contraindication for topotecan or temozolomide
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Efficacy
Time Frame:6 weeks (Arm B) or 8 weeks (Arm C)
Safety Issue:
Description:The fraction of evaluable patients who experience a PR or CR will be determined and this fraction will be reported along with an 80% and 95% confidence interval.

Secondary Outcome Measures

Measure:Safety
Time Frame:21 days (Arm B) or 28 days (Arm C)
Safety Issue:
Description:Safety of the agent will be assessed by determining the grade of adverse events noted in each patient, and reporting the fraction with grade 3 and grade 4 adverse events.
Measure:PFS, DOR and OS
Time Frame:From start of the trial until disease progresion of death.
Safety Issue:
Description:PFS will begin at the on-study date, and will consider progressions as well as death without progression as an event; OS will also begin atthe on-study date and will consider any death as an event. DOR will begin at the date that a PR or CR has been identified, and will be shown as continuing until the patient is no longer considered to beresponding.

Details

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

Trial Keywords

  • Chemosensitivity
  • DNA Damage and Replication
  • PD-1/PD-L1
  • Solid Tumors
  • Checkpoint Inhibitors

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