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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

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ClinicalTrials.gov Identifier: NCT02937818
Recruitment Status : Recruiting
First Posted : October 19, 2016
Last Update Posted : January 3, 2019
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

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.

Condition or disease Intervention/treatment Phase
Platinum Refractory Extensive-Stage Small Cell Lung Carcinoma Drug: Durvalumab and Tremelimumab Drug: AZD1775 and carboplatin (CBPT) Drug: AZD6738 and olaparib Phase 2

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  (Clinical Trial)
Estimated Enrollment : 91 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : November 28, 2016
Estimated Primary Completion Date : January 22, 2021
Estimated Study Completion Date : January 22, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: ARM A Drug: 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.

Experimental: ARM B 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.

Experimental: ARM C 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




Primary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: 3 years ]
    Overall Response Rate (ORR) using Investigator assessments according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. ORR (per RECIST 1.1 as assessed by site Investigator) is defined as the number (%) of patients with a confirmed Complete Response (CR) or confirmed Partial Response (PR) and will be based on all treated patients and will be estimated for each treatment arm with corresponding 2-sided 95% exact confidence intervals (CIs).


Secondary Outcome Measures :
  1. Duration of Response (DoR) using Investigator assessments according to RECIST 1.1 [ Time Frame: 2.5 years ]
  2. The pharmacokinetics (PK) of MEDI4736 (durvalumab). After the first and steady-state doses: area under the plasma concentration versus time curve (AUC) will be determined [ Time Frame: Up to 6 months ]
  3. Disease Control Rate (DCR) using Investigator assessments according to RECIST 1.1 [ Time Frame: 2.5 years ]
  4. Time To Response (TTR) using Investigator assessments according to RECIST 1.1 [ Time Frame: 2.5 years ]
  5. Progression Free Survival (PFS) using Investigator assessments according to RECIST 1.1 [ Time Frame: 2.5 years ]
  6. The pharmacokinetics (PK) of AZD1775 therapy. After the first and steady-state doses: area under the plasma concentration versus time curve (AUC) will be determined [ Time Frame: Up to 12 months ]
  7. The pharmacokinetics (PK) tremelimumab. After the first and steady-state doses: area under the plasma concentration versus time curve (AUC) will be determined [ Time Frame: Up to 6 months ]
  8. The pharmacokinetics (PK) of Carboplatin therapy. After the first and steady-state doses: area under the plasma concentration versus time curve (AUC) will be determined [ Time Frame: Up to 12 months ]
  9. The pharmacokinetics (PK) of MEDI4736 (durvalumab). After the first and steady-state doses: peak plasma concentration (Cmax) will be determined [ Time Frame: Up to 6 months ]
  10. The pharmacokinetics (PK) of AZD1775 therapy. After the first and steady-state doses: peak plasma concentration (Cmax) will be determined [ Time Frame: Up to 12 months ]
  11. The pharmacokinetics (PK) tremelimumab. After the first and steady-state doses: peak plasma concentration (Cmax) will be determined [ Time Frame: Up to 6 months ]
  12. The pharmacokinetics (PK) of Carboplatin therapy. After the first and steady-state doses: peak plasma concentration (Cmax) will be determined [ Time Frame: Up to 12 months ]
  13. The pharmacokinetics (PK) parameters of olaparib after single dose and at steady-state will be determined by non-compartmental analysis e.g. area under the plasma concentration versus time curve (AUC), peak plasma concentration (Cmax) [ Time Frame: Up to 12 months ]
  14. The pharmacokinetics (PK) parameters of AZD6738 after single dose and at steady-state will be determined by non-compartmental analysis e.g. area under the plasma concentration versus time curve (AUC), peak plasma concentration (Cmax) [ Time Frame: Up to 12 months ]
  15. Overall Survival (OS) [ Time Frame: 2.5 years ]


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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02937818


Contacts
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Contact: AstraZeneca Cancer Study Locator Service 1-877-400-4656 AstraZeneca@emergingmed.com

Locations
Germany
Research Site Recruiting
Gauting, Germany, 82131
Hungary
Research Site Recruiting
Kecskemét, Hungary, 6000
Research Site Recruiting
Miskolc, Hungary, 3529
Research Site Recruiting
Székesfehérvár, Hungary, 8000
Research Site Not yet recruiting
Törökbálint, Hungary, 2045
Poland
Research Site Recruiting
Poznań, Poland, 60-569
Research Site Recruiting
Warszawa, Poland, 02-781
Spain
Research Site Recruiting
Sevilla, Spain, 41009
Research Site Recruiting
Valencia, Spain, 46009
Ukraine
Research Site Recruiting
Dnipropetrovsk, Ukraine, 49102
Research Site Recruiting
Ivano-Frankivsk, Ukraine, 76018
Research Site Not yet recruiting
Kirovograd, Ukraine, 25006
Research Site Active, not recruiting
Sumy, Ukraine, 40022
Sponsors and Collaborators
AstraZeneca
Investigators
Study Director: Haiyi Jiang, M.D. AstraZeneca

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02937818     History of Changes
Other Study ID Numbers: D419QC00002
2016-001202-42 ( EudraCT Number )
First Posted: October 19, 2016    Key Record Dates
Last Update Posted: January 3, 2019
Last Verified: January 2019

Keywords provided by AstraZeneca:
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

Additional relevant MeSH terms:
Carcinoma
Lung Neoplasms
Small Cell Lung Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Olaparib
Tremelimumab
Carboplatin
Antineoplastic Agents
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action