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 Overview
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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.

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.

Official Title
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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

Conditions
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Platinum Refractory Extensive-Stage Small Cell Lung Carcinoma

Intervention / Treatment
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* Drug: Durvalumab and Tremelimumab
* Drug: AZD1775 and carboplatin (CBPT)
* Drug: AZD6738 and olaparib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARM A<br> | Drug: Durvalumab and Tremelimumab<br>* 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.<br>|
| Experimental: ARM B<br> | Drug: AZD1775 and carboplatin (CBPT)<br>* AZD1775 twice daily (oral) for 2.5 days from Day 1 + CBDP area under the curve 5 (Day1) (IV); every 3 weeks.<br>|
| Experimental: ARM C<br> | Drug: AZD6738 and olaparib<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Until disease progression [PD] (Up to 3.5 Years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | Until disease progression or data cut-off or Death (Up to 3.5 Years) | 
| Progression Free Survival (PFS) | 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) | 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 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) | 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) | 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) | 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 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) | 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) | 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) | 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) | 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 | 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 | 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) | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Platinum Refractory Extensive-Stage Carcinoma, Small Cell Lung, Platinum Refractory Extensive-Stage Oat Cell Carcinoma of Lung, Platinum Refractory Extensive-Stage Oat Cell Lung Cancer, Platinum Refractory Extensive-Stage Small Cell Cancer Of The Lung, Platinum Refractory Extensive-Stage Small Cell Lung Cancer