Primary Outcome Measures
- Efficacy [ Time Frame: 6 weeks (Arm B) or 8 weeks (Arm C) ]
The fraction of evaluable patients who experience a PR or CR will be determined and this fraction will be reported along with an 80% and 95% confidence interval.
Secondary Outcome Measures
- Safety [ Time Frame: 21 days (Arm B) or 28 days (Arm C) ]
Safety of the agent will be assessed by determining the grade of adverse events noted in each patient, and reporting the fraction with grade 3 and grade 4 adverse events. - PFS, DOR and OS [ Time Frame: From start of the trial until disease progresion of death. ]
PFS will begin at the on-study date, and will consider progressions as well as death without progression as an event; OS will also begin at the on-study date and will consider any death as an event. DOR will begin at the date that a PR or CR has been identified, and will be shown as continuing until the patient is no longer considered to be responding.
Eligibility Criteria
- 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 1.5×109/L
- platelets greater than 100×10^9/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.
- Subjects with both platinum-sensitive and platinum-refractory disease will be eligible
- Subjects who progressed on at least one prior chemotherapy.
- 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 temozo
dl - Subjects who are receiving any other investigational agents. Prior immunotherapy, topotecan and temozolomide are allowed.
