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.

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 deoxyribonucleic acid (DNA) damage response network. SCLC is also characterized by high DNA replication stress (retinoblastoma (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 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 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 (MSB0011359C) 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 non-small cell lung cancer (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 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 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.

• M7824 (Drug), also known as MSB0011359C: 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.
• Topotecan (Drug), also known as Hycamtin: Arm B: 1 mg/m(2) intravenous (IV) over 30 minutes days 1-5 on a 3-week cycle.
• Temozolomide (Drug), also known as Temodar: Arm C and progressive disease patients on Arm A: 200 mg/m(2) by mouth (PO) days 1-5 on a 4-week cycle.
• EKG (Diagnostic test), also known as Electrocardiogram: Screening and baseline.
• CT scan (Diagnostic test), also known as Computed tomography 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.
• PET scan (Diagnostic test), also known as Positron emission tomography 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.
• Acetaminophen (Drug), also known as Tylenol, Ofirmev, FeverAll: For infusion related reaction, 500-1000 mg by mouth (PO) prior to infusion.
• Antihistamines (Drug): As medically indicated.
• Diphenhydramine (Drug), also known as Benadryl, Banophen, Nytol: For infusion related reaction, 50 mg by mouth (PO) prior to infusion.
• Dexamethasone (Drug), also known as Maxidex, Ozurdex, DexPak 10 day: As medically indicated.
• Epinephrine (Drug), also known as Adrenaline: As medically indicated.

Primary outcomes

• Proportion of Evaluable Participants Who Experience a Partial Response (PR) or Complete Response (CR) Reported Along With an 80% Confidence Interval. [6 weeks (Arm B) or 8 weeks (Arm C)]: The fraction of evaluable participants who experience a PR or CR will be determined and this fraction will be reported along with an 80% confidence interval. Response was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Complete response is disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
• Proportion of Evaluable Participants Who Experience a Partial Response (PR) or Complete Response (CR) Reported Along With an 95% Confidence Interval. [6 weeks (Arm B) or 8 weeks (Arm C)]: The fraction of evaluable participants who experience a PR or CR will be determined and this fraction will be reported along with an 95% confidence interval. Response was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Complete response is disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
• Number of Participants Experiencing a Dose-limiting Toxicity (DLT) by Grade and Type [3 weeks for Arm A; First cycle (Arm B - 3 weeks and Arm C- 4 weeks)]: Fraction of participants experiencing a dose-limiting toxicity (DLT) by grade and type assessed by the CTCAE. Grade 3 is severe. Grade 4 is life threatening. Grade 5 is death related to adverse event. The occurrence of any of the following toxicities will be considered a DLT if judged by the Investigator to be possibly, probably or definitely related to study drug administration: Grade 4 non-hematologic toxicity (not laboratory). Grade 4 hematologic toxicity lasting ≥7 days. Grade 3 non-hematologic toxicity (not laboratory, specifically nausea, vomiting and diarrhea) lasting >5 days despite optimal supportive care. Febrile neutropenia Grade 3 or Grade 4. Thrombocytopenia <25,000/mm3 if associated with a bleeding event which does not result in hemodynamic instability but requires an elective platelet transfusion, or a life-threatening bleeding event which results in urgent intervention.

Secondary outcomes

• Proportion of Grade 3 and/or Grade 4 Adverse Events [Document adverse events from the first study intervention through 30 days after the participant received the last study treatment administration, approximately 30-353 days]: Safety of the agent will be assessed by determining the grade of adverse events noted in each participant and reporting the fraction with grade 3 and/or grade 4 adverse events. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Grade 3 is severe. Grade 4 is life-threatening.
• Progression Free Survival (PFS) [At 6 months]: PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. PFS will begin at the on-study date and will consider progressions as well as death without progression as an event. Progression was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions. PFS was measured using the Kaplan-Meier method and is reported along with a 95% confidence interval.
• Duration of Response (DOR) [At 6 months]: Duration of overall response is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented using the Kaplan-Meier method and reported along with a 95% confidence interval. Response is measured by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete response is disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.
• Overall Survival (OS) [maximum of 67.14 months]: OS is defined as the date of on-study to the date of death from any cause or last follow up. OS was measured using the Kaplan-Meier method and is reported along with a 95% confidence interval.

Other outcomes

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). [Adverse Events was monitored/assessed from the first study intervention through 30 days after the participant received last study treatment administration, 30 - 467 days or an average of 112.4 days.]: Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Sex: All, ages: 18 Years to 99 Years

* INCLUSION CRITERIA:
* Patients must have histologically or cytologically confirmed small cell lung cancer (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.
* Eastern Cooperative Oncology Group (ECOG) performance status greater than or equal to 2.
* Subjects must have measurable disease per Response Evaluation Criteria in Solid Tumors (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
  * Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamic-pyruvic transaminase (SGPT) less than or equal to 2.5 x upper limit of normal (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 principal investigator (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 (human immunodeficiency virus (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 Coronavirus Disease (COVID) vaccines are permitted.
* Subjects unwilling to accept blood products as medically indicated.
* Known contraindication for topotecan or temozolomide

Participant flow

Outcome results

• Proportion of Evaluable Participants Who Experience a Partial Response (PR) or Complete Response (CR) Reported Along With an 80% Confidence Interval. (Primary), Number, Proportion of participants: Arm A/M7824 (MSB0011359C) Monotherapy 0.1 (0 to 0.2216); Arm B/M7824 (MSB0011359C) Plus Topotecan 0 (0 to 0); Arm C/M7824 (MSB0011359C) Plus Temozolomide 0.2 (0.067 to 0.3324)
• Proportion of Evaluable Participants Who Experience a Partial Response (PR) or Complete Response (CR) Reported Along With an 95% Confidence Interval. (Primary), Number, Proportion of participants: Arm A/M7824 (MSB0011359C) Monotherapy 0.1 (0 to 0.2859); Arm B/M7824 (MSB0011359C) Plus Topotecan 0 (0 to 0); Arm C/M7824 (MSB0011359C) Plus Temozolomide 0.2 (0 to 0.4024)
• Number of Participants Experiencing a Dose-limiting Toxicity (DLT) by Grade and Type (Primary), Count of participants, Participants: Arm A/M7824 (MSB0011359C) Monotherapy 0; Arm B/M7824 (MSB0011359C) Plus Topotecan 0; Arm C/M7824 (MSB0011359C) Plus Temozolomide 1
• Proportion of Grade 3 and/or Grade 4 Adverse Events (Secondary), Number, Proportion of adverse events: Arm A/M7824 (MSB0011359C) Monotherapy 0.149; Arm B/M7824 (MSB0011359C) Plus Topotecan 0.246; Arm C/M7824 (MSB0011359C) Plus Temozolomide 0.1191
• Progression Free Survival (PFS) (Secondary), Median, Months: Arm A/M7824 (MSB0011359C) Monotherapy 2.31 (1.38 to 6.5); Arm B/M7824 (MSB0011359C) Plus Topotecan 1.44 (1.11 to 2.03); Arm C/M7824 (MSB0011359C) Plus Temozolomide 2.03 (1.84 to 5.79)
• Duration of Response (DOR) (Secondary), Median, Months: Arm A/M7824 (MSB0011359C) Monotherapy 3.71 (NA to NA); Arm B/M7824 (MSB0011359C) Plus Topotecan ; Arm C/M7824 (MSB0011359C) Plus Temozolomide 16.67 (3.91 to 17.11)
• Overall Survival (OS) (Secondary), Median, Months: Arm A/M7824 (MSB0011359C) Monotherapy 4.58 (2.13 to 12.78); Arm B/M7824 (MSB0011359C) Plus Topotecan 2.89 (1.87 to 5.88); Arm C/M7824 (MSB0011359C) Plus Temozolomide 8.86 (2.95 to 17.31)
• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). (Other pre specified), Count of participants, Participants: Arm A/M7824 (MSB0011359C) Monotherapy 13; Arm B/M7824 (MSB0011359C) Plus Topotecan 5; Arm C/M7824 (MSB0011359C) Plus Temozolomide 19

Adverse events

Time frame: All-Cause Mortality was monitored/assessed an average of 7.56 months. Adverse Events was monitored/assessed from the first study intervention through 30 days after the participant received last study treatment administration, 30 - 467 days or an average of 112.4 days.

Serious adverse events by term

Other adverse events by term

112 more terms not shown.

• Results publication: Fialkoff G, Takahashi N, Sharkia I, Gutin J, Hermoni N, Nirula M, Kumar R, Pongor L, Nichols S, Sciuto L, Parmar K, Desai P, Suresh P, Abel M, El Meskini R, Maoz M, Rottenberg Y, Nevo S, Nechushtan H, Peretz T, Roame D, Hubert A, Cohen JE, Salah A, Temper M, Grinshpun A, Weaver-Ohler Z, Rajan A, Figg WD Sr, Zick A, Sadeh R, Friedman N, Thomas A. Plasma nucleosome profiling reports on tumor burden and molecular subtypes in small cell lung cancer. J Clin Invest. 2026 Oct 1;136(19):e202151. doi: 10.1172/JCI202151. eCollection 2026 Oct 1. PMID 42820295

• Study Protocol and Statistical Analysis Plan (PDF, 2024-01-11)
• Informed Consent Form (PDF, 2024-01-29)

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