Clinical trial NCT02937818: 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
Official title: 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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Platinum Refractory Extensive-Stage Small Cell Lung Carcinoma
Keywords: 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
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2016-10-19
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Overall Response
timeFrame: Until disease progression [PD] (Up to 3.5 Years)
Secondary outcomes:
measure: Duration of Response (DoR)
timeFrame: Until disease progression or data cut-off or Death (Up to 3.5 Years)
measure: Percentage of Participants With Disease Control at 12 Weeks
timeFrame: At 12 Weeks
measure: Time to Response (TTR)
timeFrame: Until disease progression or data cut-off or Death (Up to 3.5 Years)
measure: Progression Free Survival (PFS)
timeFrame: Until disease progression or data cut-off or Death (Up to 3.5 Years)
measure: Overall Survival (OS)
timeFrame: Until disease progression or data cut-off or Death (Up to 3.5 Years)
measure: Time to Maximum Concentration (Tmax)
timeFrame: Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose)
measure: Maximum Concentration (Cmax)
timeFrame: Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose)
measure: Partial Area Under the Concentration-time Curve (AUC0-6)
timeFrame: Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose) and Cycle 1 Day 7 (pre-dose and post-dose)
measure: Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-t)
timeFrame: Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose) and Cycle 1 Day 7 (pre-dose and post-dose)
measure: Time to Maximum Concentration at Steady State (Tmax,ss)
timeFrame: Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)
measure: Maximum Concentration at Steady State (Cmax,ss)
timeFrame: Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)
measure: Minimum Concentration at Steady State (Cmin,ss)
timeFrame: Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)
measure: Area Under the Concentration-time Curve at Steady State (AUCss)
timeFrame: Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)
measure: Apparent Clearance of Drug at Steady State at Steady State (CLss/F)
timeFrame: Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)
measure: Serum Concentrations of Durvalumab and Tremelimumab
timeFrame: 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)
measure: Plasma Concentrations of Adavosertib and Carboplatin
timeFrame: 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)
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Other outcomes:
Locations:
city: Gauting
country: Germany
facility: Research Site
city: Kecskemét
country: Hungary
facility: Research Site
city: Miskolc
country: Hungary
facility: Research Site
city: Székesfehérvár
country: Hungary
facility: Research Site
city: Törökbálint
country: Hungary
facility: Research Site
city: Poznań
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Dnipro
country: Ukraine
facility: Research Site
city: Ivano-Frankivsk
country: Ukraine
facility: Research Site
city: Sumy
country: Ukraine
facility: Research Site
Study officials:
affiliation: AstraZeneca
name: Haiyi Jiang, M.D.
role: STUDY_DIRECTOR
References: