M7824 and Topotecan or Temozolomide in Relapsed Small Cell Lung Cancers

Summary

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 deoxyribonucleic acid (DNA) damage response network. SCLC is also characterized by high DNA replication stress (retinoblastoma (RB1) inactivation, MYC and CCNE1 activation).
* There is only one Food and Drug Administration (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 programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway can yield responses in a subset of SCLC patients, but response rates (approximately equal to 10%) are lower than non-small cell lung cancer (NSCLC) and other tumors with comparable tumor mutational burden indicating additional immunosuppressive mechanisms at play in the SCLC tumor microenvironment.
* M7824 (MSB0011359C) 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 Food and Drug Administration (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 (Eastern Cooperative Oncology Group (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 pharmacokinetic (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 cycle 1 day 1 (C1D1) and C1D15 for Arm C; pre-treatment on C1D1 and cycle 2 day 1 (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 dose-limiting toxicity (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/m(2) 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/m(2)/day on days 1-5 every 4 weeks until disease progression or a criterion in Protocol is met.

Conditions

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

Interventions

DRUG

M7824

Arm A \& B: 2400mg intravenous (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/m(2) intravenous (IV) over 30 minutes days 1-5 on a 3-week cycle.

DRUG

Temozolomide

Arm C and progressive disease patients on Arm A: 200 mg/m(2) by mouth (PO) days 1-5 on a 4-week cycle.

DIAGNOSTIC_TEST

EKG

Screening and baseline.

DIAGNOSTIC_TEST

CT scan

Computed tomography (CT) scan performed at Screening and after every 2 cycles (6 weeks) per Study Calendar for Arm B 3.5.2, Arm B 3.5.2, and/or Arm C 3.5.3 as applicable.

DIAGNOSTIC_TEST

PET scan

Positron emission tomography (PET) not mandatory - If a computed tomography (CT) scan is not sufficient to assess response, a PET scan may be added per Study Calendar for Arm A 3.5.1, Arm B 3.5.2, and/or Arm C 3.5.3 as applicable.

DRUG

Acetaminophen

For infusion related reaction, 500-1000 mg by mouth (PO) prior to infusion.

DRUG

Antihistamines

As medically indicated.

DRUG

Diphenhydramine

For infusion related reaction, 50 mg by mouth (PO) prior to infusion.

DRUG

Dexamethasone

As medically indicated.

DRUG

Epinephrine

As medically indicated.

Sponsors & Collaborators

• National Cancer Institute (NCI)

  lead NIH

Principal Investigators

• Anish Thomas, M.D. · National Cancer Institute (NCI)

Study Design

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

SEQUENTIAL

Eligibility

Min Age

18 Years

Max Age

99 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2018-09-11

Primary Completion

2022-06-01

Completion

2025-03-13

FDA Drug

Yes

Countries

• United States

Study Locations