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 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

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.

Extrapulmonary small cell cancers are extremely rare and management of systemic disease with chemotherapy is patterned after the approach used in SCLC.

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). Similarly, extrapulmonary small cell cancers have no standard treatments and it appears that although these cancers can arise by different mechanisms, they have in common high replication stress, that may be susceptible to DNA damage and immune checkpoint blockade.

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 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 (PD-L1) 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 or extrapulmonary small cell cancers.

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

Eligibility Criteria:
* INCLUSION CRITERIA:
* Patients must have histologically or cytologically confirmed SCLC or extrapulmonary small cell cancers.
* Subjects with relapsed SCLC (diagnosed with limited or extensive stage disease) with tumor progression on or after at least one prior chemotherapy. Patients with SCLC should in addition have received and have disease progression on or after prior immunotherapy.
* 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 6 months for women and 3 months for men after the last dose of study drug. Men should not donate sperm during participation in the study and for up to 3 months after the last dose of study 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 30 days prior to the first administration of study intervention. Seasonal flu vaccines that do not contain a live virus are permitted. Locally approved COVID vaccines are permitted.
* Subjects unwilling to accept blood products as medically indicated.
* Known contraindication for topotecan or temozolomide