A Phase 1/2 Study of Durvalumab(MEDI4736) and Tremelimumab in Chinese Patients With Advanced Malignancies

A Phase 1/2 Open-label, Multi-center Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Anti-tumor Activity of Durvalumab (MEDI4736) in Combination With Tremelimumab in Chinese Patients With Advanced Malignancies

A Phase 1/2 Open-label, Multi-center Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Anti-tumor Activity of Durvalumab (MEDI4736) in combination with tremelimumab in Chinese Patients with Advanced Malignancies

Study Overview

• Status: Completed
• Conditions: Advanced Malignancy
• Intervention / Treatment: Drug: durvalumab; Drug: tremelimumab + durvalumab

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Changchun, China, 130012
    • Research Site
  • Changchun, China, 130000
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 128 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Provision of informed consent prior to any study specific procedures
• Male or female, aged at least 18 years
• For Phase 1 PK cohort:

Patients with histologically or cytologically confirmed advanced and/or metastatic solid tumors other than HCC refractory or intolerable to existing standard of treatment

For Phase 2 cohort:

For nasopharyngeal carcinoma:

Patients with histologically or cytologically confirmed nasopharyngeal carcinoma must have locally advanced or metastatic disease progressed on or after at least 1 chemotherapy regimen with or without radiotherapy.

• ONLY FOR PHASE 2 PORTION: mandatory tumor sample
• No prior exposure to immune-mediated therapy including, but not limited to, other anti CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 (anti-PD-L2) antibodies, excluding therapeutic anticancer vaccines.
• Life expectancy ≥12 weeks at Day 1
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• At least 1 lesion that can be accurately measured at baseline, and that is suitable for repeated measurements as per RECIST 1.1 guidelines.
• Adequate organ and marrow function
• Hemoglobin ≥9 g/dL Absolute neutrophil count ≥1.0 × 109 /L Platelet count ≥75 × 109/L Total serum bilirubin ≤1.5×upper limit of normal (ULN) ALT and AST ≤2.5×ULN; for patients with hepatic metastases, ALT and AST ≤5×ULN Calculated creatinine clearance >40 mL/min as determined by Cockcroft-Gault (using actual body weight), or by measured 24-hour urine collection for determination of creatinine clearance.
• Evidence of post-menopausal status, or negative urinary or serum pregnancy test for female pre-menopausal patients.
• Exclusion Criteria:
• Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable. Note: Local treatment of isolated lesions for palliative intent is acceptable (eg, local surgery or radiotherapy).
• Receipt of last dose of an approved (marketed) anticancer therapy (chemotherapy, targeted therapy, biologic therapy, mAbs, etc) within 21 days prior to the first dose of study treatment. If sufficient washout time has not occurred due to the schedule or PK properties of an agent, a longer washout period will be required, as agreed upon by AstraZeneca and the Investigator.
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug.
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
• History of allogenic organ transplantation
• Any unresolved toxicity National Cancer Institute (NCI) CTCAE Version 4.03 Grade ≥2 from previous anticancer therapy
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], celiac disease, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis], Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc).
• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
• History of another primary malignancy
• History of leptomeningeal carcinomatosis
• Brain metastases or spinal cord compression unless asymptomatic or treated and stable off steroids and anti-convulsants for at least 14 days prior to study treatment.
• QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated.
• History of active primary immunodeficiency
• Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus .
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab (MEDI4736) or tremelimumab.
• Receipt of live, attenuated vaccine within 30 days prior to the first dose of IP.
• Female patients who are pregnant or breast-feeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab (MEDI4736) plus tremelimumab combination therapy or 90 days after the last dose of durvalumab (MEDI4736) monotherapy.
• Known allergy or hypersensitivity to IP or any IP excipient, or to other humanized mAbs
• Prior randomisation or treatment in a previous durvalumab (MEDI4736) and/or tremelimumab clinical study regardless of treatment arm assignment
• NSCLC patients have history of interstitial lung disease

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: durvalumab; durvalumab alone	Drug: durvalumab; durvalumab (MEDI4736) 20mg/kg via IV infusion every 4 weeks until confirmed disease progression or unacceptable toxicity
Experimental: durvalumab+tremelimumab; durvalumab plus tremelimumab	Drug: tremelimumab + durvalumab; 20 mg/kg durvalumab (MEDI4736) via IV infusion q4w and 1 mg/kg tremelimumab via IV infusion q4w for up to 4 doses/cycles, and then continue 20 mg/kg durvalumab (MEDI4736) q4w starting on Week 16 for up to confirmed disease progression

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum plasma concentration (Cmax)	Only for phase 1 portion of the study	approximately 6 months after the last evaluable patient in Phase 1 portion is first dosed
Trough plasma concentration (Ctrough)	Only for phase 1 portion of the study	approximately 6 months after the last evaluable patient is first dosed in phase 1 portion
Area under the plasma drug concentration-time curve from time zero to Day 28 post-dose (AUC 0-28)	Only for phase 1 portion of the study	approximately 6 months after the last evaluable patient is first dosed in phase 1 portion
Adverse event		Approximately 12 months after the last evaluable patient from Ph 1 is 1st dosed or the last patient has withdrawn from study or the study discontinued by Sponsor
Objective response rate (ORR)	Only for phase 2 portion of the study (Phase 2 part withdrawn without initiation)	Approximately 12 months after the last evaluable patient is dosed, or the last patient has withdrawn from the study or the study is discontinued by the sponsor.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anti-drug antibody (ADA)		approximately 12 months after the last evaluable patient is first dosed, or the last patient has withdrawn from the study, or the study is discontinued by the Sponsor
Anti-drug antibody neutralizing antibodies (ADA nAB)		approximately 12 months after the last evaluable patient is first dosed, or the last patient has withdrawn from the study, or the study is discontinued by the Sponsor
Complete response/Partial response/Stable disease/Progressive disease	Only for phase 1 portion of the study	approximately 6 months after the last evaluable patient is first dosed in phase 1 portion
Overall survival (OS)	Only for phase 2 portion of the study (Phase 2 part withdrawn without initiation)	approximately 12 months after the last evaluable patient is first dosed, or the last patient has withdrawn from the study, or the study is discontinued by the Sponsor

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
PD-L1 status	Only for phase 2 portion of the study (Phase 2 part withdrawn without initiation)	through study completion, an average of 2 years
CD8+ T cells	Only for phase 2 portion of the study (Phase 2 part withdrawn without initiation)	through study completion, an average of 2 years
IFNγ	Only for phase 2 portion of the study (Phase 2 part withdrawn without initiation)	through study completion, an average of 2 years

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Study Director: Urban Scheuring, AstraZeneca GMD IO, Melbourn Science Park, Melbourn, Royston, Hertfordshire, SG8 6HB, UK

Publications and helpful links

Helpful Links

• Results of this clinical trial are available on www.astrazenecaclinicaltrials.com

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2016
• Primary Completion (Actual): January 28, 2018
• Study Completion (Actual): November 26, 2020

Study Registration Dates

• First Submitted: November 8, 2016
• First Submitted That Met QC Criteria: November 28, 2016
• First Posted (Estimate): December 1, 2016

Study Record Updates

• Last Update Posted (Actual): August 18, 2021
• Last Update Submitted That Met QC Criteria: August 12, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Durvalumab; Tremelimumab; Antibodies, Monoclonal
• Other Study ID Numbers: D419AC00006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.