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M7824 and Topotecan or Temozolomide in Relapsed Small Cell Lung Cancers

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ClinicalTrials.gov Identifier: NCT03554473
Recruitment Status : Recruiting
First Posted : June 13, 2018
Last Update Posted : July 3, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Carcinoma, Small Cell Lung Cancer Small Cell Lung Cancer Drug: M7824 Drug: Topotecan Drug: Temozolomide Phase 1 Phase 2

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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


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 57 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Safety Run-In and Phase II Trial of M7824 and Topotecan or Temozolomide in Relapsed Small Cell Lung Cancers
Actual Study Start Date : September 11, 2018
Estimated Primary Completion Date : January 15, 2023
Estimated Study Completion Date : January 15, 2024


Arm Intervention/treatment
Experimental: Arm A/M7824 Monotherapy
M7824 (IV) monotherapy once every 21 days on a21-day cycle.
Drug: M7824
Arm A: 1800 mg IV over 1 hour every 3 weeks on a 3-week cycle for n=6 or 2400mg IV over up to 120 minutes every 3 weeks on a 3-week cycle for n=4. Arm B: 2400mg IV over up to 120 minutes every 3 weeks on a 3-week cycle. Arm C: 1200 mg IV over 1 hour every 2 weeks on a 4-week cycle.

Experimental: Arm B/M7824 plus topotecan
M7824 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.
Drug: M7824
Arm A: 1800 mg IV over 1 hour every 3 weeks on a 3-week cycle for n=6 or 2400mg IV over up to 120 minutes every 3 weeks on a 3-week cycle for n=4. Arm B: 2400mg IV over up to 120 minutes every 3 weeks on a 3-week cycle. Arm C: 1200 mg IV over 1 hour every 2 weeks on a 4-week cycle.

Drug: Topotecan
Arm B: 1 mg/m2 IV over 30 minutes days 1-5 on a 3-week cycle.

Experimental: Arm C/M7824 plus temozolomide safety
M7824 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.
Drug: M7824
Arm A: 1800 mg IV over 1 hour every 3 weeks on a 3-week cycle for n=6 or 2400mg IV over up to 120 minutes every 3 weeks on a 3-week cycle for n=4. Arm B: 2400mg IV over up to 120 minutes every 3 weeks on a 3-week cycle. Arm C: 1200 mg IV over 1 hour every 2 weeks on a 4-week cycle.

Drug: Temozolomide
Arm C: 200 mg/m2 PO days 1-5 on a 4-week cycle




Primary Outcome Measures :
  1. Efficacy [ Time Frame: 6 weeks (Arm B) or 8 weeks (Arm C) ]
    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 :
  1. Safety [ Time Frame: 21 days (Arm B) or 28 days (Arm C) ]
    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.

  2. PFS, DOR and OS [ Time Frame: From start of the trial until disease progresion of death. ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03554473


Contacts
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Contact: Santhana B Webb, R.N. (240) 858-3165 santhana.webb@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Anish Thomas, M.D. National Cancer Institute (NCI)

Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03554473     History of Changes
Other Study ID Numbers: 180110
18-C-0110
First Posted: June 13, 2018    Key Record Dates
Last Update Posted: July 3, 2019
Last Verified: July 1, 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Chemosensitivity
DNA Damage and Replication
PD-1/PD-L1
Solid Tumors
Checkpoint Inhibitors
Additional relevant MeSH terms:
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Lung Neoplasms
Small Cell Lung Carcinoma
Carcinoma, Small Cell
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Temozolomide
Topotecan
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors