Study of Durvalumab+Olaparib or Durvalumab After Treatment With Durvalumab and Chemotherapy in Patients With Lung Cancer (ORION) (ORION)

• ClinicalTrials.gov Identifier: NCT03775486
• Recruitment Status: Recruiting
• First Posted: December 14, 2018
• Last Update Posted: October 2, 2019
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Study Description

Brief Summary:

This is a randomized, double-blind, multi-center, global Phase II study to determine the efficacy and safety of Durvalumab plus Olaparib combination therapy compared with Durvalumab monotherapy as maintenance therapy in patients whose disease has not progressed following Standard of Care (SoC) platinum-based chemotherapy with Durvalumab as first-line treatment in patients with Stage IV non small-cell lung cancer (NSCLC) with tumors that lack activating epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) fusions.

Condition or disease	Intervention/treatment	Phase
Non-small Cell Lung Cancer NSCLC	Drug: Durvalumab; Drug: Placebo for Olaparib; Drug: Olaparib; Drug: Nab-paclitaxel+carboplatin; Drug: Gemcitabine+carboplatin; Drug: Pemetrexed+carboplatin; Drug: Gemcitabine+cisplatin; Drug: Pemetrexed+cisplatin	Phase 2

Detailed Description:

Adult patients with a histologically or cytologically documented advanced NSCLC not amenable to curative surgery or radiation with tumors that lack activation EGFR mutations and ALK fusions are eligible for enrollment. During the initial therapy phase, patients will receive treatment with Durvalumab along with the Investigator's choice of platinum-based doublet therapy for squamous NSCLC (nab-paclitaxel plus carboplatin or gemcitabine plus carboplatin/cisplatin) and non-squamous NSCLC (nab-paclitaxel plus carboplatin or pemetrexed plus carboplatin/cisplatin) for 4 cycles. Patients who have completed 4 cycles and not progressed throughout the initial therapy phase will be randomized in a 1:1 ratio into the maintenance phase of the study to receive either Durvalumab plus placebo or Durvalumab plus Olaparib maintenance therapy. Patients will receive maintenance treatment until specific discontinuation criteria are met, including clinical disease progression (as assessed by the Investigator) or RECIST 1.1-defined radiological Progressive Disease (PD), unacceptable toxicity, and withdrawal of consent. Tumor evaluation scans will be performed until objective disease progression as efficacy assessments. All patients will be followed for survival until the end of the study.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 327 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase II Randomized, Multi-Center, Double-Blind, Global Study to Determine the Efficacy and Safety of Durvalumab Plus Olaparib Combination Therapy Compared With Durvalumab Monotherapy as Maintenance Therapy in Patients Whose Disease Has Not Progressed Following Standard of Care Platinum-Based Chemotherapy With Durvalumab in First Line Stage IV Non Small Cell Lung Cancer (ORION)
• Actual Study Start Date: December 21, 2018
• Estimated Primary Completion Date: June 2, 2021
• Estimated Study Completion Date: June 2, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Durvalumab/Olaparib Combination Therapy; Durvalumab/Olaparib Combination Therapy: Durvalumab/SoC chemotherapy (initial therapy phase) followed by Durvalumab/Olaparib (maintenance phase)	Drug: Durvalumab; Initial therapy phase: IV infusion q3w for 4 cycles. Maintenance phase: IV infusion q4w.; Other Name: MEDI4736 (Durvalumab); Drug: Olaparib; 150-mg tablets (2 × 150-mg tablets for 300-mg dose) 100-mg tablet available if dose reductions are required; Other Name: AZD2281 (Olaparib); Drug: Nab-paclitaxel+carboplatin; Standard of Care chemotherapy (squamous and non-squamous patients); Drug: Gemcitabine+carboplatin; Standard of Care chemotherapy (squamous patients only); Drug: Pemetrexed+carboplatin; Standard of Care chemotherapy (non-squamous patients only); Drug: Gemcitabine+cisplatin; Standard of Care chemotherapy (squamous patients only); Drug: Pemetrexed+cisplatin; Standard of Care chemotherapy (non-squamous patients only)
Experimental: Durvalumab Monotherapy; Durvalumab Monotherapy: Durvalumab/SoC chemotherapy (initial therapy phase) followed by Durvalumab/placebo (maintenance phase)	Drug: Durvalumab; Initial therapy phase: IV infusion q3w for 4 cycles. Maintenance phase: IV infusion q4w.; Other Name: MEDI4736 (Durvalumab); Drug: Placebo for Olaparib; Matching tablet; Other Name: Placebo; Drug: Nab-paclitaxel+carboplatin; Standard of Care chemotherapy (squamous and non-squamous patients); Drug: Gemcitabine+carboplatin; Standard of Care chemotherapy (squamous patients only); Drug: Pemetrexed+carboplatin; Standard of Care chemotherapy (non-squamous patients only); Drug: Gemcitabine+cisplatin; Standard of Care chemotherapy (squamous patients only); Drug: Pemetrexed+cisplatin; Standard of Care chemotherapy (non-squamous patients only)

Outcome Measures

Primary Outcome Measures :

1. Progression-free survival [ Time Frame: Approximately 2 years after randomization ]
   Progression-free survival (PFS) defined as time from date of randomization until the date of objective radiological disease progression using RECIST 1.1 or death (by any cause in the absence of progression).

Secondary Outcome Measures :

1. Overall survival [ Time Frame: Approximately 4 years after randomization ]
   Overall survival (OS) defined as time from date of randomization until the date of death by any cause.
2. Objective response rate [ Time Frame: Approximately 2 years after randomization. ]
   Objective response rate (ORR) defined as percentage of patients with an Investigator-assessed of complete response (CR) or partial response (PR) after randomization.
3. Duration of response [ Time Frame: Approximately 2 years after randomization. ]
   Duration of response (DoR) defined as time from the date of first documented response following randomization until the first date of documented progression or death in the absence of disease progression.
4. PFS in homologous recombination repair related gene mutation (HRRm) population [ Time Frame: Approximately 3 years after randomization ]
   PFS in HRRm population defined as time from date of randomization until the date of objective radiological disease progression in HRRm population using RECIST 1.1 or death (by any cause in the absence of progression).
5. Concentration of Durvalumab [ Time Frame: PK of Durvalumab will be assessed at 3, 6, 12, 16 and 20 weeks after start of treatment and every 12 weeks thereafter until 3 months after last dose of durvalumab ]
   Concentration of Durvalumab: Pharmacokinetic (PK) of Durvalumab
6. Change from baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-Lung Cancer (LC)13 [ Time Frame: Health-related quality of life (HRQoL) will be assessed at 4 weeks after randomization and every 4 weeks thereafter until 3 months after treatment discontinuation ]
   Disease-related symptoms and HRQoL assessed by change from baseline (for maintenance phase) in EORTC QLQ-LC13.
7. Change from baseline in EORTC Quality of Life Questionnaire (QLQ) QLQ-C30 [ Time Frame: Health-related quality of life (HRQoL) will be assessed at 4 weeks after randomization and every 4 weeks thereafter until 3 months after treatment discontinuation ]
   Disease-related symptoms and HRQoL assessed by change from baseline (for maintenance phase) in EORTC QLQ-C30
8. Presence of anti-drug antibodies (ADA) for Durvalumab [ Time Frame: ADA will be assessed at 3, 6, 12, 16 and 20 weeks after start of treatment and every 12 weeks thereafter until 3 and 6 months after last dose of durvalumab ]
   Presence of anti-drug antibodies (ADA) for Durvalumab.
9. 'Number of Participants with Treatment-Related Adverse Events as Assessed by Common Terminology Criteria for Adverse Events (CTCAE) [ Time Frame: Approximately 2 years after randomization ]
   'Number of Participants with Treatment-Related Adverse Events as Assessed by Common Terminology Criteria for Adverse Events (CTCAE)

Eligibility Criteria

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

Criteria

Inclusion Criteria:

- Histologically or cytologically documented Stage IV NSCLC not amenable to curative surgery or radiation.

Patients must have tumors that lack activating EGFR mutations and ALK fusions.

• (WHO)/(ECOG) performance status of 0 or 1
• No prior chemotherapy or any other systemic therapy for Stage IV NSCLC
• Adequate organ and marrow function without blood transfusions in the past 28 days,
• At least 1 tumor lesion, not previously irradiated, that can be accurately measured as per RECIST 1.1.

Key Inclusion criteria for randomization to maintenance treatment:

• Documented radiographic evidence of CR, PR, or Stable Disease (SD) as per Investigator-assessed RECIST 1.1 following 4 cycles of platinum-based chemotherapy.
• Creatinine Clearance (CrCl) ≥51 mL/min calculated by Cockcroft-Gault equation or measured by 24-hour urine collection.
• Ability to swallow whole oral medications.

Exclusion criteria

• Mixed small-cell lung cancer and sarcomatoid variant NSCLC histology.
• Prior exposure to any chemotherapy agents (except chemotherapy or chemoradiation for non-metastatic disease), polyadenosine 5'diphosphoribose [poly (ADP ribose)] polymerase (PARP) therapy, or immunomediated therapy
• Active or prior documented autoimmune or inflammatory disorders.
• Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of Investigational Product (IP)
• untreated (CNS) metastases and/or carcinomatous meningitis
• Active infection.

Exclusion criteria to be randomized to maintenance treatment:

• Inability to complete 4 cycles of platinum-based chemotherapy for any reason or discontinuation of Durvalumab during initial therapy.

Contacts and Locations

Contacts

Contact: AstraZeneca Clinical Study Information Center; 1-877-240-9479; information.center@astrazeneca.com

  Show 77 Study Locations

Sponsors and Collaborators

AstraZeneca

Investigators

• Principal Investigator: Myung-Ju Ahn, MD; Sungkyunkwan University School of Medicine, 135-710, Seoul, Korea
• Study Director: Mark Lanasa, MD, PHD; One MedImmune Way,Gaithersburg,Maryland,United States

More Information

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT03775486 History of Changes
• Other Study ID Numbers: D9102C00001; 2018-003460-30 ( EudraCT Number )
• First Posted: December 14, 2018
• Last Update Posted: October 2, 2019
• Last Verified: September 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AstraZeneca:

NSCLC; Durvalumab; Olaparib; Maintenance; Homologous Recombination Repair (HRR)

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Gemcitabine; Cisplatin; Carboplatin; Pemetrexed; Durvalumab; Olaparib; Antibodies, Monoclonal; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antiviral Agents; Anti-Infective Agents; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors; Antineoplastic Agents, Immunological