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

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

72 participants

Study Classification

INTERVENTIONAL

Study Start Date

2016-11-28

Study Completion Date

2023-11-27

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Platinum Refractory Extensive-Stage Small Cell Lung Carcinoma

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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ARM A

Group Type EXPERIMENTAL

Durvalumab and Tremelimumab

Intervention Type DRUG

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.

ARM B

Group Type EXPERIMENTAL

AZD1775 and carboplatin (CBPT)

Intervention Type DRUG

AZD1775 twice daily (oral) for 2.5 days from Day 1 + CBDP area under the curve 5 (Day1) (IV); every 3 weeks.

ARM C

Group Type EXPERIMENTAL

AZD6738 and olaparib

Intervention Type DRUG

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

Interventions

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Durvalumab and Tremelimumab

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.

Intervention Type DRUG

AZD1775 and carboplatin (CBPT)

AZD1775 twice daily (oral) for 2.5 days from Day 1 + CBDP area under the curve 5 (Day1) (IV); every 3 weeks.

Intervention Type DRUG

AZD6738 and olaparib

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

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

* 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.

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

• Able and willing to swallow oral medication.

Exclusion Criteria

* 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.

* 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.

* 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.

* 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

Minimum Eligible Age

18 Years

Maximum Eligible Age

130 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No