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

December 7, 2023 updated by: AstraZeneca

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

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.

Study Overview

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.

Study Type

Interventional

Enrollment (Actual)

72

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Gauting, Germany, 82131
        • Research Site
      • Kecskemét, Hungary, 6000
        • Research Site
      • Miskolc, Hungary, 3529
        • Research Site
      • Székesfehérvár, Hungary, 8000
        • Research Site
      • Törökbálint, Hungary, 2045
        • Research Site
      • Poznań, Poland, 60-569
        • Research Site
      • Warszawa, Poland, 02-781
        • Research Site
      • Sevilla, Spain, 41009
        • Research Site
      • Valencia, Spain, 46009
        • Research Site
      • Dnipro, Ukraine, 49102
        • Research Site
      • Ivano-Frankivsk, Ukraine, 76018
        • Research Site
      • Sumy, Ukraine, 40022
        • Research Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 130 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion criteria (applicable to all arms)

  • Adults with histologically or cytologically documented ED SCLC who have demonstrated progressive disease either during first-line platinum-based chemotherapy (platinum refractory) or within 90 days of completing platinum based-chemotherapy (platinum resistant) and have not received further treatment.
  • Brain metastases must be asymptomatic or treated and stable off steroids and anti-convulsants for at least 1 month prior to study treatment.
  • At least 1 lesion, not previously irradiated, that can be accurately measured at baseline (per RECIST v 1.1 guidelines)
  • Life expectancy of at least 8 weeks.
  • WHO/ ECOG PS of 0-1 at enrollment.

Inclusion criteria (Arm A specific)

  • Body weight >30 kg.
  • No prior exposure to immune mediated therapy, excluding therapeutic anticancer vaccines.

Inclusion criteria (Arm B specific) • Able and willing to swallow oral medication.

Inclusion criteria (Arm C specific)

• Able and willing to swallow oral medication.

Exclusion criteria (applicable to all arms):

  • Participation in another clinical study, major surgery, radiation therapy within 28 days.
  • Any condition that, in the opinion of the Investigator, would interfere with the evaluation of the IP or interpretation of patient safety or study results.
  • Uncontrolled intercurrent illness, including but not limited to interstitial lung disease.
  • History of another primary malignancy, leptomeningeal carcinomatosis or spinal cord compression.

Exclusion criteria (Arm A specific)

  • Active autoimmune disease, including a paraneoplastic syndrome.
  • Active or prior documented autoimmune or inflammatory disorders.
  • Any unresolved toxicity (CTCAE Grade >2) from previous anticancer therapy.
  • Active infection including tuberculosis, HIV, Hepatitis B or C.

Exclusion criteria (Arm B specific)

  • Prior exposure to any WEE1 inhibitors.
  • Products known to be sensitive to CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors/inducers of CYP3A4. Co-administration of rosuvastatin, atorvastatin, simvastatin and lovastatin, aprepitant or fosaprepitant or any herbal preparations. Grapefruit and Seville oranges should be avoided while taking AZD1775.
  • Any known hypersensitivity or contraindication to IP or CBDP.
  • QTcF > 470 msec or congenital long QT syndrome.
  • Any current or within 6 months cardiac diseases NYHA ≥ Class 2: unstable angina pectoris, congestive heart failure, acute MI, conduction abnormality not controlled with pacemaker or medication, significant ventricular or supraventricular arrhythmias.
  • A recent history of Torsades de pointes.

Exclusion criteria (Arm C specific)

  • Cytotoxic chemotherapy within 21 days of Cycle 1 Day 1 is not permitted
  • Previous treatment with a PARP inhibitor (including olaparib) or ATR inhibitor
  • Concomitant use of known strong CYP3A inhibitors and moderate CYP3A inhibitors
  • Concomitant use of known strong and moderate CYP3A inducers
  • Persisting (> 4 weeks) severe pancytopenia due to previous therapy
  • Cardiac dysfunction
  • Refractory nausea and vomitting, chronic gastrointenstinal diseases or previous significant bowel resection
  • Patients with uncontrolled seizures
  • Intenstinal obstruction or CTCAE grade 3 or grade 4 GI bleeding within 4 weeks before dosing

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: ARM A
Durvalumab + tremelimumab via intravenous (IV) infusion every 4 weeks (q4w), starting on Week 0, for up to a total of 4 months (4 cycles) followed by durvalumab monotherapy via IV infusion q4w, starting on Week 16 until PD, or for other discontinuation criteria.
Experimental: ARM B
AZD1775 twice daily (oral) for 2.5 days from Day 1 + CBDP area under the curve 5 (Day1) (IV); every 3 weeks.
Experimental: ARM C
AZD6738 once a day (oral) for 7 days from Day 1 + olaparib twice a day(oral) for 28 days from Day 1, every 4 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Overall Response
Time Frame: 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.
Until disease progression [PD] (Up to 3.5 Years)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Duration of Response (DoR)
Time Frame: 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.
Until disease progression or data cut-off or Death (Up to 3.5 Years)
Percentage of Participants With Disease Control at 12 Weeks
Time Frame: 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.
At 12 Weeks
Time to Response (TTR)
Time Frame: 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.
Until disease progression or data cut-off or Death (Up to 3.5 Years)
Progression Free Survival (PFS)
Time Frame: 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.
Until disease progression or data cut-off or Death (Up to 3.5 Years)
Overall Survival (OS)
Time Frame: 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.
Until disease progression or data cut-off or Death (Up to 3.5 Years)
Time to Maximum Concentration (Tmax)
Time Frame: Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose)
Time to maximum concentration for ceralasertib and olaparib are reported.
Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose)
Maximum Concentration (Cmax)
Time Frame: Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose)
Maximum concentration for ceralasertib and olaparib are reported.
Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose)
Partial Area Under the Concentration-time Curve (AUC0-6)
Time Frame: 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.
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 (AUC0-t)
Time Frame: 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.
Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose) and Cycle 1 Day 7 (pre-dose and post-dose)
Time to Maximum Concentration at Steady State (Tmax,ss)
Time Frame: 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.
Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)
Maximum Concentration at Steady State (Cmax,ss)
Time Frame: 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.
Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)
Minimum Concentration at Steady State (Cmin,ss)
Time Frame: 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.
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 (AUCss)
Time Frame: 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.
Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)
Apparent Clearance of Drug at Steady State at Steady State (CLss/F)
Time Frame: 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.
Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)
Serum Concentrations of Durvalumab and Tremelimumab
Time Frame: 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.
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)
Plasma Concentrations of Adavosertib and Carboplatin
Time Frame: 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.
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)
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame: 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.
Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Investigators

  • Study Director: Haiyi Jiang, M.D., AstraZeneca

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 28, 2016

Primary Completion (Actual)

June 22, 2020

Study Completion (Actual)

November 27, 2023

Study Registration Dates

First Submitted

October 5, 2016

First Submitted That Met QC Criteria

October 17, 2016

First Posted (Estimated)

October 19, 2016

Study Record Updates

Last Update Posted (Actual)

December 22, 2023

Last Update Submitted That Met QC Criteria

December 7, 2023

Last Verified

December 1, 2023

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

IPD Sharing Time Frame

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

IPD Sharing Access Criteria

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Platinum Refractory Extensive-Stage Small Cell Lung Carcinoma

Clinical Trials on Durvalumab and Tremelimumab

3
Subscribe