M7824 and Topotecan or Temozolomide in Relapsed Small Cell Lung Cancers

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

- 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. Performance Status Criteria.

- Subjects must have measurable disease,

- 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, 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