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Navitoclax

Patients receive navitoclax PO QD and vistusertib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Vistusertib

Christine L Hann

This phase I/II trial studies the best dose and side effects of navitoclax and how well it works when given together with vistusertib in treating patients with small cell lung cancer and solid tumors that have come back (relapsed). Drugs used in chemotherapy, such as navitoclax, 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. Vistusertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving navitoclax and vistusertib may work better than navitoclax alone in treating patients with small cell lung cancer and solid tumors.

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of the combination of navitoclax and vistusertib in patients with advanced solid tumors. (Phase I) II. To determine the maximum tolerated dose (MTD), dose limiting toxicities (DLT), and recommended phase 2 doses (RP2D) of navitoclax and vistusertib. (Phase I) III. To determine the objective response rate (ORR), defined as complete plus partial response, of the combination of navitoclax and vistusertib in patients with recurrent small cell lung cancer (SCLC). (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the pharmacokinetics of navitoclax and vistusertib when administered together. (Phase I) II. To observe and record anti-tumor activity. (Phase I) III. To confirm the safety and tolerability of navitoclax and vistusertib at the RP2D. (Phase II) IV. To estimate progression free survival (PFS) and overall survival (OS) of the combination of navitoclax and vistusertib at the RP2D. (Phase II) V. To estimate disease control rate (DCR) of the combination of navitoclax and vistusertib at the RP2D. (Phase II)

CORRELATIVE OBJECTIVES:

I. To assess pharmacodynamic changes in levels of phosphorylated 4EBP1 (p4EBP1) the ratio of p4EBP1 to total (p4EBP1/4EBP1) in paired pre-treatment and on-treatment biopsies at the RP2D. (Phase II) II. To correlate changes in BAX and MCL-1 with response. (Phase II) III. To estimate the baseline inter-patient variability in p4EBP1, pS6, BAX, and MCL-1. (Phase II) IV. To explore exposure-response relationships between navitoclax and vistusertib exposure and the pharmacodynamic endpoints (safety, efficacy, and laboratory correlatives). (Phase II)

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive navitoclax orally (PO) once daily (QD) and vistusertib PO twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 8-12 weeks for up to 2 years.

Navitoclax and Vistusertib in Treating Patients With Relapsed Small Cell Lung Cancer and Other Solid Tumors

Phase 1/2 Study of Navitoclax Plus Vistusertib in Patients With Relapsed Small Cell Lung Cancer (SCLC) and Other Solid Tumors

Descriptive statistics and box plots with jittered data points will be used to visualize all raw data. Will be assessed with paired t-tests.

Exploratory correlative studies with pharmacodynamic (biological endpoints, toxicity and efficacy) will be analyzed using nonparametric statistics.

Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0. The number of participants with dose limiting toxicities at each dose level will be reported with exact binomial 95% confidence intervals. All patients who receive at least 1 dose of both study drugs, regardless of their eligibility for the study, will be evaluable for toxicity.

Defined as Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. partial response or complete response, of the combination in patients with recurrent small cell lung cancer. The ORR will be reported with its corresponding 95% confidence interval.

Concentrations of each study agent present in the blood at the specified time point are reported for each study agent.

Graded by NCI CTCAE v 4.0. The number of participants with toxicities by grade in the phase 2 study will be reported with exact binomial 95% confidence intervals.

Based on RECIST 1.1. Standard life table methods will be used to analyze PFS. We will report the one-year and median PFS with 95% confidence intervals.

Standard life table methods will be used to analyze OS. We will report the one-year and median OS with 95% confidence intervals.

Based on RECIST 1.1. The proportion of patients achieving disease control will be reported with exact 95% binomial confidence intervals.

National Cancer Institute (NCI)

Navitoclax 150 mg po qd + Vistusertib 35 mg po bid

Phase 1 - Dose Level 1

Navitoclax 250 mg po qd + Vistusertib 35 mg po bid

Phase 1 - Dose Level 2

Phase 2

Patients receive navitoclax 150 mg orally (PO) once a day (QD) and vistusertib 35 mg PO twice a day (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients receive navitoclax 250 mg PO QD and vistusertib 35 mg PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Weight

Height

Body Surface Area (BSA)

Primary site of disease

Eastern Cooperative Oncology Group (ECOG) Performance Status

Only 1 participant was enrolled to Phase 2 before the study was closed to accrual for low accrual.

Judy Murray

Phase 1 participants were included in this analysis. Please see AE section for additional details.

Number of Participants With Dose Limiting Toxicities (Phase I)

Overall Response Rate (ORR) (Phase II)

Navitoclax average of individual steady-state trough concentration (avg Cmin,ss)

Navitoclax Cycle 1 Day 1 Concentration 6 hours after dose (C6h)

Navitoclax Cycle 1 Day 15 Concentration 6 hours after dose (C6h)

Navitoclax Cycle 1 Day 15 maximum concentration (Cmax)

Vistusertib average of individual steady-state trough concentration (avg Cmin,ss)

Vistusertib Cycle 1 Day 1 Concentration 2 hours after dose (C2h)

Vistusertib Cycle 1 Day 15 Concentration 2 hours after dose (C2h)

Participants in either Phase who received Navitoclax 150 mg.

Navitoclax 150 mg + Vistusertib 35 mg

Participants in either Phase who received Navitoclax 250 mg

Navitoclax 250 mg + Vistusertib 35 mg

Participants who initially received Navitoclax 250 mg but were reduced to navitoclax 150 mg.

Navitoclax 250 mg Reduced to 150 mg + Vistusertib 35 mg

Participants in both phases were included. Some data was not collected at each timepoint.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Navitoclax and Vistusertib in Treating Patients With Relapsed Small Cell Lung Cancer and Other Solid Tumors	NCT03366103	Metastatic Mali... Recurrent Lung ... Recurrent Malig... Refractory Mali... Stage III Lung ... Stage IIIA Lung... Stage IIIB Lung... Stage IV Lung S... Unresectable So...	Navitoclax Vistusertib	18 Years -	National Cancer Institute (NCI)
Navitoclax and Vistusertib in Treating Patients With Relapsed Small Cell Lung Cancer and Other Solid Tumors	NCT03366103	Metastatic Mali... Recurrent Lung ... Recurrent Malig... Refractory Mali... Stage III Lung ... Stage IIIA Lung... Stage IIIB Lung... Stage IV Lung S... Unresectable So...	Navitoclax Vistusertib	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for stage iii lung small cell carcinoma, by american joint committee on cancer (ajcc) v7