Talazoparib and Low-Dose Temozolomide in Treating Patients with Relapsed or Refractory Extensive-Stage Small Cell Lung Cancer
This phase II trial studies how effective talazoparib and temozolomide are for treating patients with extensive-stage small cell lung cancer that has come back (relapsed) after an initial chemotherapy treatment. Talazoparib, a PARP inhibitor, may stop the growth of tumor cells by preventing them from repairing their DNA. Chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving talazoparib and temozolomide may work better in treating patients with extensive-stage small cell lung cancer than either one alone.
Inclusion Criteria
- 2ND LINE COHORT: Male or female >= 18 years of age and willing and able to provide informed consent.
- 2ND LINE COHORT: Cytologically or histologically confirmed small cell lung cancer (SCLC) with extensive-stage disease. This includes all high-grade neuroendocrine cancers of the lung.
- 2ND LINE COHORT: Relapsed (progressed within 6 months) or refractory (progressed during or within 4 weeks of completing 1st line platinum based regimen).
- 2ND LINE COHORT: Participants that were previously treated for limited stage small cell lung cancer and have recurred are eligible.
- 2ND LINE COHORT: Measurable disease, as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
- 2ND LINE COHORT: Archival or fresh tissue biopsy available for exploratory analyses. Archival tissue must be collected within the past 3 years from cycle 1 day 1 (C1D1). Fresh tissue must be collected within 30 days from C1D1.
- 2ND LINE COHORT: Eastern Cooperative Oncology Group (ECOG) performance status of =< 1.
- 2ND LINE COHORT: Able to swallow the study drugs, has no known intolerance to study drugs or excipients, and able to comply with study requirements.
- 2ND LINE COHORT: Female participants of childbearing potential must have a negative pregnancy test at screening and must agree to use a highly effective birth control method from the time of the first study drug treatment through 7 months after the last study drug treatment.
- 2ND LINE COHORT: Male participants must use effective contraception when having sex from the time of the first study drug treatment through a minimum of 4 months after the last study drug treatment. Contraception should be considered for a non-pregnant female partner of childbearing potential.
- 2ND LINE COHORT: Male and female participants must agree not to donate sperm or eggs, respectively, from the first study drug treatment through 4 months and 7 months after the last study drug treatment, respectively.
- 2ND LINE COHORT: Female participants may not be breastfeeding at baseline through a minimum of 1 month after the last study drug treatment.
- 2ND LINE COHORT: Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
- 2ND LINE COHORT: Platelets >= 100 x 10^9/L
- 2ND LINE COHORT: Hemoglobin >= 9 g/dL without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
- 2ND LINE COHORT: Glomerular filtration rate (by Cockroft-Gault or equivalent estimation) >= 30 mL/min
- 2ND LINE COHORT: Serum total bilirubin =< 1.5 X upper limit or normal (ULN) OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 ULN
- 2ND LINE COHORT: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for participants with liver metastases
- 2ND LINE COHORT: International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless participant is receiving anticoagulant therapy, as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
- 2ND LINE COHORT: Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless participant is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants
- 1ST LINE COHORT: Male or female >= 18 years of age and willing and able to provide informed consent.
- 1ST LINE COHORT: Cytologically or histologically confirmed SCLC with extensive-stage disease. This includes all high-grade neuroendocrine cancers of the lung.
- 1ST LINE COHORT: Participants that were previously treated for limited stage small cell lung cancer and have recurred are eligible if there has been at least a 1 year progression free interval since completion of the prior therapy.
- 1ST LINE COHORT: Measurable disease, as per RECIST 1.1.
- 1ST LINE COHORT: Provision of an archival tissue sample. If unavailable, we request, but do not require a new biopsy.
- 1ST LINE COHORT: ECOG performance status of =< 1.
- 1ST LINE COHORT: Able to swallow the study drugs, has no known intolerance to study drugs or excipients, and able to comply with study requirements.
- 1ST LINE COHORT: Female participants of childbearing potential must have a negative pregnancy test at screening and must agree to use a highly effective birth control method from the time of the first study drug treatment through 7 months after the last study drug treatment.
- 1ST LINE COHORT: Male participants must use effective contraception when having sex from the time of the first study drug treatment through a minimum of 4 months after the last study drug treatment. Contraception should be considered for a non-pregnant female partner of childbearing potential
- 1ST LINE COHORT: Male and female participants must agree not to donate sperm or eggs, respectively, from the first study drug treatment through 4 months and 7 months after the last study drug treatment, respectively.
- 1ST LINE COHORT: Female participants may not be breastfeeding from the time of the first study drug treatment through a minimum of 1 month after the last study drug treatment.
- 1ST LINE COHORT: Absolute neutrophil count (ANC) >= 1.5 x 10^9/L.
- 1ST LINE COHORT: Platelets >= 100 x 10^9/L
- 1ST LINE COHORT: Hemoglobin >= 9 g/dL without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
- 1ST LINE COHORT: Glomerular filtration rate (by Cockroft-Gault or equivalent estimation) >= 30 mL/min
- 1ST LINE COHORT: Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 ULN.
- 1ST LINE COHORT: AST (SGOT) and ALT (SGPT) =< 2.5 X ULN OR =< 5 X ULN for participants with liver metastases
- 1ST LINE COHORT: International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless participant is receiving anticoagulant therapy, as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
- 1ST LINE COHORT: Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless participant is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants
Exclusion Criteria
- 2ND LINE COHORT: Has not recovered (recovery is defined as CTCAEv5 grade =< 1 or return to baseline) from the acute toxicities of previous therapy, except treatment-related alopecia or laboratory abnormalities otherwise meeting eligibility requirements.
- 2ND LINE COHORT: Best response of progressive disease per RECIST 1.1 to first-line platinum doublet chemotherapy (i.e., patient must have had stable disease, partial response or complete response on their first restaging scans after starting first-line chemotherapy).
- 2ND LINE COHORT: Has received more than 1 line of cytotoxic therapy * Prior immunotherapy and targeted therapies (including rovalpituzumab tesirine) are allowed. * For limited-stage disease that progresses after 12 months from the end of initial cytotoxic treatment, the initial cytotoxic treatment will not be counted towards the maximum of one prior line of cytotoxic treatment. For limited stage disease that progresses within 12 months from the end of initial cytotoxic treatment will count as one prior line of cytotoxic treatment.
- 2ND LINE COHORT: Prior treatment with a PARP inhibitor (not including iniparib) or temozolomide.
- 2ND LINE COHORT: Use of antineoplastic therapies within 14 days before study treatment initiation.
- 2ND LINE COHORT: Use of any other investigational agent within 14 days before study treatment initiation.
- 2ND LINE COHORT: Received radiation therapy < 14 days before study treatment initiation (single fraction palliative radiotherapy is allowed without a washout). * Prior thoracic irradiation and prophylactic cranial irradiation are allowed.
- 2ND LINE COHORT: Major surgery within 14 days before study treatment initiation.
- 2ND LINE COHORT: Diagnosis of myelodysplastic syndrome (MDS).
- 2ND LINE COHORT: Gastrointestinal disorder affecting absorption.
- 2ND LINE COHORT: Current or anticipated use of a prohibited P-gp inhibitor or P-gp inducer or BCRP inhibitors.
- 2ND LINE COHORT: History of another cancer within 2 years before study treatment initiation, with the exception of fully treated cancers unlikely to affect the assessment of the study treatment safety or efficacy including early stage breast, prostate, nonmelanomatous skin, thyroid, cervix and endometrial cancer.
- 2ND LINE COHORT: Progressive or symptomatic brain metastases. Brain metastases that have been radiated, and that are asymptomatic, and on a stable or decreasing dose of steroids are allowed. Leptomeningeal disease is excluded.
- 2ND LINE COHORT: Any condition (concurrent disease, infection, or comorbidity) that interferes with ability to participate in the study, causes undue risk, or complicates the interpretation of safety data, in the opinion of the investigator.
- 1ST LINE COHORT: Has received any prior systemic therapy for the current diagnosis; * Prior treatment for limited stage disease is allowed if progression occurred after 12 months from the end of initial cytotoxic treatment.
- 1ST LINE COHORT: Prior treatment with a PARP inhibitor (not including iniparib) or temozolomide.
- 1ST LINE COHORT: Use of antineoplastic therapies within 14 days before study treatment initiation.
- 1ST LINE COHORT: Use of any other investigational agent within 14 days before study treatment initiation.
- 1ST LINE COHORT: Received radiation therapy < 14 days before study treatment initiation (single fraction palliative radiotherapy is allowed without a washout). * Prior thoracic irradiation and prophylactic cranial irradiation are allowed.
- 1ST LINE COHORT: Major surgery within 14 days before study treatment initiation.
- 1ST LINE COHORT: Diagnosis of myelodysplastic syndrome (MDS).
- 1ST LINE COHORT: Gastrointestinal disorder affecting absorption
- 1ST LINE COHORT: Current or anticipated use of a prohibited P-gp inhibitor or P-gp inducer or BCRP inhibitors
- 1ST LINE COHORT: History of another cancer within 2 years before study treatment initiation, with the exception of fully treated cancers unlikely to affect the assessment of the study treatment safety or efficacy including early stage breast, prostate, nonmelanomatous skin, thyroid, cervix and endometrial cancer
- 1ST LINE COHORT: Progressive or symptomatic brain metastases. Brain metastases that have been radiated, and that are asymptomatic, and on a stable or decreasing dose of steroids are allowed. Leptomeningeal disease is excluded.
- 1ST LINE COHORT: Any condition (concurrent disease, infection, or comorbidity) that interferes with ability to participate in the study, causes undue risk, or complicates the interpretation of safety data, in the opinion of the investigator.
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03672773.
PRIMARY OBJECTIVE:
I. Evaluate the efficacy of talazoparib in combination with temozolomide as measured by objective response rate (ORR). (Second-line cohort)
II. Evaluate the efficacy of talazoparib in combination with temozolomide in patients who are treatment naive as measured by progression-free survival (PFS). (First-line cohort)
SECONDARY OBJECTIVES:
I. To evaluate the efficacy of talazoparib plus temozolomide as measured by PFS, overall survival, duration of response, and time to response. (Second-line cohort)
II. To evaluate the safety, tolerability of talazoparib plus temozolomide. (Second-line cohort)
III. To evaluate the pharmacokinetics of talazoparib when given in combination with temozolomide. (Second-line cohort)
IV. To evaluate patient reported outcomes per the Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE [Trademark]). (Second-line cohort)
V. To evaluate overall response rate (ORR), overall survival (OS), duration of response (DOR), time to response (TTR). (First-line cohort)
VI. To evaluate patient reported outcomes (PROs) per the Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE). (First-line cohort)
VII. To evaluate objective response rate and progression-free survival on the second line regimen (ORR-2 and PFS-2). (First-line cohort)
VIII. To evaluate safety and tolerability in all evaluable patients who received at least one dose of study regimen. Toxicities are defined by the Common Terminology Criteria for Adverse Events version (V)5.0 (CTCAE 5.0). (First-line cohort)
EXPLORATORY OBJECTIVE:
I. To identify potential biomarkers associated with response to study drug treatment. (Both cohorts)
OUTLINE:
Patients receive temozolomide orally (PO) on days 1-5 and talazoparib PO once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) and magnetic resonance imaging (MRI) throughout the trial. Patients also undergo blood sample collection during screening and on study and may optionally undergo a tissue biopsy on study.
After completion of study treatment, patients are followed up at 30 days and then up to 1 year.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUCLA / Jonsson Comprehensive Cancer Center
Principal InvestigatorJonathan W. Goldman
- Primary ID18-001387
- Secondary IDsNCI-2018-01409, TRIO-US L-07
- ClinicalTrials.gov IDNCT03672773