Safety, Tolerability and Pharmacokinetics of AZD1775 (Adavosertib) Plus MEDI4736 (Durvalumab) in Patients With Advanced Solid Tumours

NCT02617277 | Completed Phase 1 DMC

• 2 other identifiers: D6015C00002REFMAL 412
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 3

Brief Summary

This study will assess the safety, tolerability, and pharmacokinetics of AZD1775 (adavosertib) given orally in combination with intravenous MEDI4736 (durvalumab). Secondly, the immunogenicity, pharmacodynamics, and preliminary anti-tumour activity will be determined in patients with refractory solid tumours.

Conditions

Advanced Solid Tumours

Keywords

AZD1775; MEDI4736; AZD1775 + MEDI4736; Advanced Solid Tumours; Adavosertib; Durvalumab

Outcome Measures

Primary Outcomes (1)

• The incidence of Dose Limiting Toxicities (DLTs)

  DLTs are defined as: 1. Grade 4 haematologic toxicity for ≥7 days, including infection with febrile neutropenia, or Grade 4 thrombocytopenia. 2. Grade 3 thrombocytopenia associated with Grade ≥2 bleeding. 3. Non-haematologic toxicity ≥Grade 3. 4. Grade 3 nausea, vomiting, or diarrhoea that does not respond within 48 hours. 5. Grade 4 nausea, vomiting, and diarrhoea. 6. ALT or AST ≥5 x but ≤8 x ULN that does not resolve to Grade 2 within 5 days. ALT or AST \>8 x ULN or total bilirubin \>5 x ULN is a DLT regardless of duration. 7. AST or ALT \>3 x ULN and concurrent increase in total bilirubin \> 2 x ULN (Hy's Law) without evidence of cholestasis or alternative explanations (viral hepatitis, disease progression in the liver). 8. Grade ≥2 pneumonitis that does not resolve to ≤ Grade 1 within 7 days. 9. Clinically significant or unacceptable toxicity that does not respond to supportive care, or results in a disruption of dosing for \>7 days.

  Up to 28 Days

Secondary Outcomes (12)

• The incidence and severity of treatment emergent adverse events (TEAEs) graded according to NCI CTCAE v4.03

  Throughout the study (approximately 18 months).

• Change from baseline in physical examination findings

  Throughout the study (approximately 18 months).

• Change from baseline in clinical chemistry, hematology, and coagulation parameters

  Throughout the study (approximately 18 months).

• Change from baseline in vital signs

  Throughout the study (approximately 18 months).

• Determine the presence of Anti-Drug Antibodies (ADA) to MEDI4736 (durvalumab).

  Throughout the study (approximately 18 months).

Study Arms (4)

Dose Schedule A

EXPERIMENTAL

In Schedule A, patients will receive MEDI4736 (durvalumab) by intravenous on Day 1, and AZD1775 (adavosertib) twice daily orally on Days 1-5 and Days 15-19 of a 28-day cycle. In all dose schedules, dexamethasone will be administered as an anti-emetic on the first day of the AZD1775 (adavosertib).

Drug: AZD1775; Drug: MEDI4736

Dose Schedule B

EXPERIMENTAL

In Schedule B, patients will receive MEDI4736 (durvalumab) by intravenous on Day 1, and AZD1775 (adavosertib) twice daily orally on Days 15-17 and Days 22-24 of a 28-day cycle. In Schedule B there will be a 7-day AZD1775 (adavosertib) lead-in to enable serial PK measurements prior to initiating MEDI4736 on Day 1. In all dose schedules, dexamethasone will be administered as an anti-emetic on the first day of the AZD1775 (adavosertib) consecutive dosing day blocks including the lead-in portion of Schedules B, C, and D. Additional alternative dose levels and/or schedules may also be explored if emerging data suggest these would be more appropriate.

Drug: AZD1775; Drug: MEDI4736

Dose Schedule C

EXPERIMENTAL

In Schedule C, patients will receive MEDI4736 (durvalumab) by intravenous on Day 1, and AZD1775 (adavosertib) twice daily orally on Days 8-10, Days 15-17, and Days 22-24 of a 28-day cycle. In Schedule C there will be a 7-day AZD1775 (adavosertib) lead-in to enable serial PK measurements prior to initiating MEDI4736 (durvalumab) on Day 1. In all dose schedules, dexamethasone will be administered as an anti-emetic on the first day of the AZD1775 (adavosertib) consecutive dosing day blocks including the lead-in portion of Schedules B, C, and D. Additional alternative dose levels and/or schedules may also be explored if emerging data suggest these would be more appropriate.

Drug: AZD1775; Drug: MEDI4736

Dose Schedule D

EXPERIMENTAL

In Schedule D, patients will receive MEDI4736 (durvalumab) by intravenous on Day 1, and AZD1775 (adavosertib) one time per day orally on Days 15-19, and Days 22-26 of a 28-day cycle. In Schedule D there will be a 9-day lead-in period with AZD1775 (adavosertib) being dosed on Days -9 to -5 to enable serial PK measurements prior to initiating MEDI4736 (durvalumab) on Day 1. In all dose schedules, dexamethasone will be administered as an anti-emetic on the first day of the AZD1775 (adavosertib) consecutive dosing day blocks including the lead-in portion of Schedules B, C, and D. Additional alternative dose levels and/or schedules may also be explored if emerging data suggest these would be more appropriate.

Drug: AZD1775; Drug: MEDI4736

Interventions

AZD1775 DRUG

AZD1775 (adavosertib) is available in capsules for oral administration.

Also known as: Adavosertib

Dose Schedule A; Dose Schedule B; Dose Schedule C; Dose Schedule D

MEDI4736 DRUG

MEDI4736 (durvalumab) will be administered by IV infusion.

Also known as: Durvalumab

Dose Schedule A; Dose Schedule B; Dose Schedule C; Dose Schedule D

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Capable of giving informed consent.
• Males and females ≥18 years of age.
• Weight ≥ 30 kg.
• Histologic confirmation of a solid tumour, excluding lymphoma, refractory to standard therapy or for which no standard of care regimen exists.
• Measurable or non-measureable disease according to RECIST v1.1.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
• Baseline laboratory values within 7 days prior to receiving study drugs (without transfusion support):
• Absolute neutrophil count (ANC) ≥1500/μL
• Haemoglobin (HgB) ≥9 g/dL
• Platelets ≥100,000/μL
• Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 2.5 x Upper Limit of Normal (ULN).
• Serum bilirubin within normal limits (WNL) or ≤ 1.5 x ULN in patients with liver metastases; or total bilirubin ≤ 3.0 x ULN with direct bilirubin WNL in patients with well documented Gilbert's Syndrome.
• Serum creatinine ≤ 1.5 x ULN, or creatinine clearance (CrCl) ≥ 40 mL/min as calculated by Cockcroft-Gault method.
• Fertile females of child-bearing potential who agree to use adequate contraceptive measures from 2 weeks prior to the study and until 1 month after the last dose of AZD1775 (adavosertib) or 3 months after the last dose of MEDI4736 (durvalumab), whichever is later, who are not breastfeeding, and who have a negative serum or urine pregnancy test within 3 days prior to the start of study treatment.
• Male patients must agree to use at least one medically acceptable form of contraception for the duration of the study and for 3 months after the last dose of AZD1775 (adavosertib) and MEDI4736 (durvalumab), whichever is later.

You may not qualify if:

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• Previous enrolment in this study.
• Concurrent enrolment in another interventional clinical study.
• Participation in another interventional clinical study or study with an investigational product during the last 28 days or 5 half-lives whichever is shorter.
• Major surgical procedures (as defined by the Investigator) ≤28 days of beginning study treatment, or minor surgical procedures (as defined by the Investigator) ≤7 days. No waiting period required following Port-a-Cath placement. Note: Local surgery of isolated lesions for palliative intent is acceptable.
• Palliative radiation therapy completed ≤ 7 days prior to start of study drugs.
• No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal anti-cancer radiotherapy \[except for palliative local radiotherapy\]), biological therapy or other novel agent is permitted while the patient is receiving study medication. Patients on luteinizing hormone-releasing hormone (LHRH) analogue treatment for more than 6 months are allowed entry into the study and can continue this treatment during the study.
• Any unresolved NCI CTCAE Grade \>1 toxicity from prior therapy (except alopecia or anorexia). Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with AZD1775 (adavosertib) or MEDI4736 (durvalumab) may be included after consultation with the Medical Monitor.
• Inability to swallow oral medication.
• Brain metastases or spinal cord compression unless the patient is stable (asymptomatic, no evidence of new or emerging brain metastases) and off steroids for at least 14 days prior to start of study treatment. Following radiotherapy and/or surgery, patients with brain metastases must wait 4 weeks following the intervention and must confirm stability with imaging before enrolment. Patients with suspected brain metastases at screening should have a CT/MRI of the brain prior to study entry. Brain metastases will not be recorded as RECIST target lesions (TL) at baseline.
• History of leptomeningeal carcinomatosis.
• Ascites requiring intervention (e.g. need for paracentesis or Tenckhoff catheter).
• History of primary immunodeficiency.
• History of tuberculosis.
• Organ transplant that requires the use of immunosuppressive treatment.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (3)

Research Site

Denver, Colorado, 80218, United States

Location

Research Site

Sarasota, Florida, 34232, United States

Location

Research Site

Nashville, Tennessee, 37203, United States

Location

Related Publications (1)

• Patel MR, Falchook GS, Wang JS, Imedio ER, Kumar S, Miah K, Mugundu GM, Jones SF, Spigel DR, Hamilton EP. Open-Label, Multicenter, Phase I Study to Assess Safety and Tolerability of Adavosertib Plus Durvalumab in Patients with Advanced Solid Tumors. Target Oncol. 2025 Jan;20(1):127-138. doi: 10.1007/s11523-024-01110-8. Epub 2024 Nov 19.

  PMID: 39560862 DERIVED

MeSH Terms

Interventions

adavosertib; durvalumab

Study Officials

• Manish Patel, M.D.

  Florida Cancer Specialists

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 26, 2015
• First Posted: November 30, 2015
• Study Start: December 28, 2015
• Primary Completion: April 22, 2019
• Study Completion: February 17, 2026
• Last Updated: March 4, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• 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.
• 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.

Locations

US (3)