A Phase II, Study to Determine the Preliminary Efficacy of Novel Combinations of Treatment in Patients With Platinum Refractory Extensive-Stage Small-Cell Lung Cancer

Phase 2

Completed

Conditions: Platinum Refractory Extensive-Stage Small Cell Lung Carcinoma

Interventions: Drug: AZD1775 and carboplatin (CBPT)
Drug: Durvalumab and Tremelimumab
Drug: AZD6738 and olaparib

Registration Number: NCT02937818

Lead Sponsor: AstraZeneca

Brief Summary: Study design This is a Phase II, open-label, multi-drug, multi-center, multi-arm, signal-searching study in patients with extensive-stage small-cell lung cancer (SCLC) who have refractory or resistant disease from prior platinum-based chemotherapy.

Detailed Description: This study is modular in design, allowing evaluation of the preliminary efficacy, safety, tolerability, and immunogenicity of novel combinations of immunotherapies and/or deoxyribonucleic acid (DNA) damage repair inhibitors in patients with platinum refractory or resistant extensive-stage-disease SCLC. Patients who have progressive disease (PD) during first-line platinum-based chemotherapy (platinum refractory) or PD within 90 days after completing first-line platinum-based chemotherapy (platinum resistant) will be enrolled to the study. The primary objective of the study is to assess the preliminary efficacy of each treatment arm based on objective response rate (ORR).

This study consists of a number of arms (sub-studies), each evaluating the efficacy, safety, and tolerability of a specific agent or combination. This study was initially open with 2 arms (Arms A and B), and additional arms may open, provided there is compelling rationale for the combination and safe and tolerable doses and schedules have been determined from ongoing Phase I studies. There are 2 pre-defined arms:

A. Durvalumab + tremelimumab followed by durvalumab monotherapy B. AZD1775 + carboplatin (CBDP)

Further arm was added in amendment 3:

C. AZD6738 + olaparib Amendment #4 was updated with possibility to allow expansion of any arm, to a total of 40 eligible subjects, based on Review Committee assessment of data from the first 20 subjects (from Stage 1 and Stage 2). Currently Arm A will enroll 20 additional patients into expansion.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 72

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ARM B	AZD1775 and carboplatin (CBPT)	-
ARM A	Durvalumab and Tremelimumab	-
ARM C	AZD6738 and olaparib	-

Primary Outcome Measures

Name	Time	Method
Number of Participants With Overall Response	Until disease progression [PD] (Up to 3.5 Years)	Overall Response Rate (ORR) using Investigator assessments according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. ORR was defined as the number (percentage) of participants with a confirmed Complete Response (CR) or confirmed Partial Response (PR) and was estimated for each treatment arm with corresponding 2-sided 95% exact confidence intervals (CIs). A confirmed response of CR/PR meant that a response of CR/PR was recorded at one visit and confirmed by repeat imaging, preferably at the next regularly scheduled imaging visit, and not less than 4 weeks after the visit when the response was first observed, with no evidence of progression between the initial and CR/PR confirmation visit.

Secondary Outcome Measures

Name	Time	Method
Duration of Response (DoR)	Until disease progression or data cut-off or Death (Up to 3.5 Years)	The DoR was defined as the time from the date of first documented response (which was subsequently confirmed) CR/PR until the date of documented progression, or death in the absence of disease progression. The DoR in participants with confirmed objective response are reported.
Progression Free Survival (PFS)	Until disease progression or data cut-off or Death (Up to 3.5 Years)	The PFS (per RECIST 1.1 according to the Investigator's assessment) was defined as the time from the date of the first dose of study treatment until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from allocated therapy or received another anti-cancer therapy prior to progression.
Time to Maximum Concentration (Tmax)	Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose)	Time to maximum concentration for ceralasertib and olaparib are reported.
Partial Area Under the Concentration-time Curve (AUC0-6)	Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose) and Cycle 1 Day 7 (pre-dose and post-dose)	Partial area under the concentration-time curve for ceralasertib and olaparib are reported.
Percentage of Participants With Disease Control at 12 Weeks	At 12 Weeks	The disease control rate (DCR) at 12 weeks was defined as the percentage of participants who had a best objective response of CR or PR in the first 13 weeks or who had demonstrated stable disease (SD) for a minimum interval of 11 weeks following the start of study treatment. The DCR was determined programmatically based on RECIST 1.1 using site Investigator data and all data up until the first progression event.
Overall Survival (OS)	Until disease progression or data cut-off or Death (Up to 3.5 Years)	The OS was defined as the time from the date of the first dose of study treatment until death due to any cause.
Time to Response (TTR)	Until disease progression or data cut-off or Death (Up to 3.5 Years)	The TTR (per RECIST 1.1 as assessed by the Investigator) was defined as the time from the date of first dose until the first date of documented response.
Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-t)	Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose) and Cycle 1 Day 7 (pre-dose and post-dose)	Area under the concentration-time curve from time zero to the last measurable concentration for Ceralasertib and Olaparib are reported.
Time to Maximum Concentration at Steady State (Tmax,ss)	Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)	Time to maximum concentration at steady state for Ceralasertib and Olaparib are reported.
Serum Concentrations of Durvalumab and Tremelimumab	Durvalumab: Cycle 1 (each cycle was 4 weeks) Day 1(post-dose); Cycle 2 Day 1(pre-dose); Cycle 5 Day 1 (pre-dose); Tremelimumab: Cycle 1 (each cycle was 4 weeks) Day 1 (post-dose); Cycle 2 Day 1 (pre-dose); Cycle 5 Day 1 (No dose); Cycle 7 Day 1 (No dose)	Serum concentrations of Durvalumab and Tremelimumab are reported.
Maximum Concentration (Cmax)	Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose)	Maximum concentration for ceralasertib and olaparib are reported.
Maximum Concentration at Steady State (Cmax,ss)	Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)	Maximum concentration at steady state for Ceralasertib and Olaparib are reported.
Apparent Clearance of Drug at Steady State at Steady State (CLss/F)	Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)	Area under the concentration-time curve at steady state at steady state for Ceralasertib and Olaparib are reported.
Minimum Concentration at Steady State (Cmin,ss)	Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)	Minimum concentration at steady state for Ceralasertib and Olaparib are reported.
Area Under the Concentration-time Curve at Steady State (AUCss)	Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)	Area under the concentration-time curve at steady state at steady state for Ceralasertib and Olaparib are reported.
Plasma Concentrations of Adavosertib and Carboplatin	Adavosertib: Cycle 1 (each cycle was 21 days) Day 3 (pre-dose and post-dose); Cycle 3 Day 3 (pre-dose and post-dose); Carboplatin: Cycle 1 (each cycle was 21 days) Day 1 (post-dose)	Plasma concentrations of Adavosertib and Carboplatin are reported.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. SAE is an AE that results in any untoward medical occurrence that results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, or is a significant medical event.