M7824 and Topotecan or Temozolomide in Relapsed Small Cell Lung Cancers
Status:
Suspended
Trial end date:
2025-01-15
Target enrollment:
Participant gender:
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 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