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

AstraZeneca72 enrolled

Overview

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.

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

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Platinum Refractory Extensive-Stage Small Cell Lung Carcinoma

Interventions

Durvalumab and TremelimumabDRUG

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.

AZD1775 and carboplatin (CBPT)DRUG

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

AZD6738 and olaparibDRUG

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

Eligibility

Sex: ALLMin age: 18 YearsMax age: 130 Years

Medical Language ↔ Plain English

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

Locations (12)

Research Site

Gauting, Germany

Research Site

Kecskemét, Hungary

Research Site

Miskolc, Hungary

Research Site

Székesfehérvár, Hungary

Outcomes

Primary Outcomes

Number of Participants With Overall Response

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.

Time frame: Until disease progression [PD] (Up to 3.5 Years)

Secondary Outcomes

Duration of Response (DoR)

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.

Time frame: Until disease progression or data cut-off or Death (Up to 3.5 Years)

Percentage of Participants With Disease Control 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.

Time frame: At 12 Weeks

Time to Response (TTR)

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.

Time frame: Until disease progression or data cut-off or Death (Up to 3.5 Years)

Data from ClinicalTrials.gov

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