Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Skin and Connective Tissue Diseases

Digestive System Diseases

Gland and Hormone Related Diseases

Rare Diseases

Carcinoma, Non-Small-Cell Lung

Breast Neoplasms

Carcinoma

Small Cell Lung Carcinoma

Pancreatic Neoplasms

Adenocarcinoma

Carcinoma, Small Cell

Lung Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Breast Diseases

Skin Diseases

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Small Cell Lung Cancer

Pancreatic Cancer

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Olaparib

Poly(ADP-ribose) Polymerase Inhibitors

Maleic acid

Misonidazole

Cediranib

Enzyme Inhibitors

Protein Kinase Inhibitors

Antiprotozoal Agents

Antiparasitic Agents

Patients receive cediranib maleate PO QD on day 1. Patients undergoing FMISO scan also receive olaparib PO BID beginning the day after the second FMISO scan and the rest of the patients receive olaparib PO BID beginning day 4 of cycle 1. Cycles repeat every 28 days (35 days for cycle 1) in the absence of disease progression or unacceptable toxicity.

18F-Fluoromisonidazole

Cediranib Maleate

Laboratory Biomarker Analysis

Positron Emission Tomography

Joseph W Kim

This phase II trial studies cediranib maleate in combination with olaparib in treating patients with solid tumors that have spread to other parts of the body (advanced/metastatic) or cannot be removed by surgery (unresectable), including breast cancer, non-small cell lung cancer, small cell lung cancer, and pancreatic cancer. Cediranib maleate and olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cediranib maleate may also block the flow of oxygen to the tumor, and may help make the tumor more sensitive to olaparib.

PRIMARY OBJECTIVE:

I. To determine the objective response rate (ORR) of cediranib (cediranib maleate) plus olaparib in combination in patients with advanced or metastatic solid tumors of the following tumor types: non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), pancreatic ductal adenocarcinoma (PDAC), and small cell lung cancer (SCLC).

SECONDARY OBJECTIVES:

I. To assess the safety and tolerability of oral administration of cediranib in combination with olaparib in patients with select advanced solid tumors.

II. To estimate progression free survival (PFS) in each tumor cohort.

EXPLORATORY OBJECTIVES:

I. To estimate the prevalence of the mutations of deoxyribonucleic acid (DNA) repair genes in tumors using the BROCA panel and to correlate tumor regression with mutations status. (Integrated) II. To evaluate changes in tumor hypoxia on cediranib treatment compared to baseline by \[F-18\] fluoromisonidazole (FMISO) positron emission tomography/computed tomography (PET/CT) in patients with NSCLC.

III. To evaluate levels of angiogenesis/inflammatory markers including VEGF at baseline and on treatment.

IV. To evaluate levels of circulating tumor deoxyribonucleic acid (ctDNA) at baseline and on treatment.

OUTLINE:

Patients receive cediranib maleate orally (PO) once daily (QD) on day 1. Patients undergoing FMISO scan also receive olaparib PO twice daily (BID) beginning the day after the second FMISO scan and the rest of the patients receive olaparib PO BID beginning day 4 of cycle 1. Cycles repeat every 28 days (35 days for cycle 1) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks. Patients who discontinue the study treatment for reasons other than disease progression or withdrawal of consent will continue to be followed every 4 weeks until disease progression, start of new therapy, or death, whichever occurs first.

A Phase 2 Study of Cediranib in Combination With Olaparib in Advanced Solid Tumors

In the first 20 endpoint-evaluable patients with non-small cell lung cancer and 20 endpoint-evaluable patients with triple negative breast cancer, the exploratory analyses will be done using Fisher's exact tests, Mann-Whitney U tests or McNemar's test depending on the type of data observed.

Measured by 18F-fluoromisonidazole positron emission tomography/computed tomography scans (non-small cell lung cancer). For the pre- and post-cediranib therapy outcome analysis, paired t- test or Wilcoxon signed-rank test will be applied for the continuous variables.

Will be assessed using paired t- test or Wilcoxon signed-rank.

Measured by Response Evaluation Criteria in Solid Tumors version 1.1. The exact two-sided 95% confidence interval for the objective response rate will be reported.

Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Descriptive statistics, including means, standard deviations, and ranges for continuous parameters, as well as percentages and frequencies for categorical parameters, will be presented. Adverse medical events will be tabulated. National Cancer Institute toxicity grade 3 and grade 4 laboratory abnormalities will be listed.

Estimated using the Kaplan-Meier method with the 95% confidence intervals. Thomas and Grunkemeier confidence interval will be reported. The possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease on the survival data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.

AstraZeneca

National Cancer Institute (NCI)

Symptoms and General Pathology

Recurrence

Disease Attributes

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.

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
A Phase 2 Study of Cediranib in Combination With Olaparib in Advanced Solid Tumors	NCT02498613	Advanced Malign... Metastatic Lung... Metastatic Lung... Metastatic Panc... Metastatic Trip... Pancreatic Duct... Stage III Breas... Stage III Lung ... Stage III Lung ... Stage III Pancr... Stage IIIA Brea... Stage IIIA Lung... Stage IIIA Lung... Stage IIIB Brea... Stage IIIB Lung... Stage IIIB Lung... Stage IIIC Brea... Stage IV Breast... Stage IV Lung N... Stage IV Lung S... Stage IV Pancre... Triple-Negative... Unresectable Lu... Unresectable Pa... Unresectable Pa... Unresectable Tr...	18F-Fluoromison... Cediranib Malea... Laboratory Biom... Olaparib Positron Emissi...	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)
A Phase 2 Study of Cediranib in Combination With Olaparib in Advanced Solid Tumors	NCT02498613	Advanced Malign... Metastatic Lung... Metastatic Lung... Metastatic Panc... Metastatic Trip... Pancreatic Duct... Stage III Breas... Stage III Lung ... Stage III Lung ... Stage III Pancr... Stage IIIA Brea... Stage IIIA Lung... Stage IIIA Lung... Stage IIIB Brea... Stage IIIB Lung... Stage IIIB Lung... Stage IIIC Brea... Stage IV Breast... Stage IV Lung N... Stage IV Lung S... Stage IV Pancre... Triple-Negative... Unresectable Lu... Unresectable Pa... Unresectable Pa... Unresectable Tr...	18F-Fluoromison... Cediranib Malea... Laboratory Biom... Olaparib Positron Emissi...	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 iv lung small cell carcinoma ajcc v7