Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Gastrointestinal Agents

All Drugs and Chemicals

Emetics

Dexamethasone

Durvalumab

Dexamethasone acetate

Adavosertib

Antineoplastic Agents, Immunological

Enzyme Inhibitors

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).

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.

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.

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.

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

AZD1775

MEDI4736 (durvalumab) will be administered by IV infusion.

MEDI4736

Manish Patel, M.D.

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.

This is a Phase I, multi-center, dose-escalation study to assess the safety, tolerability and pharmacokinetics of oral therapy with AZD1775 (adavosertib) when combined with a fixed-dose of MEDI4736 (durvalumab). Immunogenicity, pharmacodynamics, and preliminary anti-tumour activity in patients with refractory solid tumours will also be investigated. In the initial design of this study a novel combination of AZD1775 (adavosertib) and MEDI4736 (durvalumab) was tested. The starting dose of AZD1775 (adavosertib) was 125 mg BID, over 5 days with 9 days off in 14-day cycles. This was designated Schedule A. This dose was not well tolerated. Two of six patients experienced dose limiting toxicity (DLT). The protocol was amended to include three additional dosing schedules. designated Schedules B, C, and D. In Schedule B patients will receive MEDI4736 (durvalumab) on Day 1, AZD1775 (adavosertib) on Days 15-17 and Days 22-24 of a 28-day cycle. In Schedule C, patients will receive MEDI4736 (durvalumab) on Day 1, AZD1775 (adavosertib) on Days 8-10, Days 15-17 and Days 22-24 of 28-day cycles. In Schedule D, patients will receive MEDI4736 (durvalumab) on Day 1 and AZD1775 (adavosertib) on Days 15-19 and Days 22-26 of a 28-day cycle. AZD1775 (adavosertib) will be dosed on a maximum of 6 days (Schedule B), 9 days (Schedule C), or 10 days (Schedule D) in each 28-day cycle. In all schedules, dexamethasone will be administered as an anti-emetic on the first day of each of the AZD1775 (adavosertib) consecutive dosing day blocks including the lead-in portion for Schedules B, C, and D. AZD1775 (adavosertib) will be administered at least 1 week after MEDI4736 (durvalumab) administration. Three to six patients will be enrolled in dose level 1 of Schedule B and evaluated for safety over a 28-day cycle prior to opening Schedule C dose level 1 for enrolment. Following safety evaluation of three to six patients in Schedule C dose level 1, a decision will be made by the Safety Review Team (SRT) to move forward with one or both schedules for further dose escalation. Three to six patients will be enrolled in Schedule D dose level 1 and evaluated for safety over a 28-day cycle. Patients in Schedule D will be evaluated for escalation independently of those in Schedules A, B, and C. Dose escalation will continue until identification of the Maximum Tolerated Dose (MTD). Once the MTD is determined this cohort will be expanded to a total of 18 patients to collect further safety data and for preliminary assessment of efficacy. Alternative dose levels/cohorts and/or schedules may be explored if emerging data suggest these would be more appropriate. The first day of Cycle 1 in Schedules B, C, and D will be preceded by a lead-in period of AZD1775 (adavosertib) monotherapy to enable serial sampling for assessment of pharmacokinetic parameters.

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

A Phase I Study Assessing the Safety, Tolerability and Pharmacokinetics of AZD1775 (Adavosertib) in Combination With MEDI4736 (Durvalumab) in Patients With Advanced Solid Tumours

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.

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.

A complete physical examination will be performed on Day 1 of each cycle and at the End-of-Treatment (EOT) visit. The examination will include an assessment of general appearance; abdomen, skin, head and neck; lymph nodes, and thyroid; and respiratory, cardiovascular, musculoskeletal and neurological systems.

Blood samples for monitoring of clinical chemistry parameters and determination of haematology will be taken at screening, Days 1, 8, 15, and 22 of Cycle 1, Days 1, 8, and 15 of each cycle thereafter, and at the end-of-treatment visit.

Resting heart rate, blood pressure, respiration rate, temperature, and weight at the screening visit. Height will be measured at the screening visit only. Vital signs and weight should be obtained Day 1 of each treatment cycle and at the EOT visit.

The presence of Anti-Drug Antibodies (ADA) to MEDI4736 (durvalumab) will be determined as a measure of the immunogenicity of MEDI4736 in combination with AZD1775 (adavosertib).

The preliminary anti-tumour activity of AZD1775 (adavosertib) when combined with MEDI4736 (durvalumab) in patients with advanced solid tumours will be determined by the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1.

The objective response rate (ORR) is defined as the number of the patients with a confirmed best overall response of Complete Response (CR) or Partial Response (PR) divided by the number of patients in the efficacy analysis set.

The preliminary anti-tumour activity of AZD1775 (adavosertib) when combined with MEDI4736 (durvalumab) in patients with advanced solid tumours will be determined by the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1.

Progression-free survival (PFS) is defined as the time from date of first dose of MEDI4736 until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from therapy or receives another anti-cancer therapy prior to progression. Patients who have not progressed or died at the time of analysis will be censored at the latest date of assessment from their last evaluable RECIST assessment.

The preliminary anti-tumour activity of AZD1775 (adavosertib) when combined with MEDI4736 (durvalumab) in patients with advanced solid tumours will be determined by the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1.

The disease control rate (DCR) is defined as the percentage of patients in the efficacy analysis set with a confirmed best overall response of CR or PR, or a best overall response of Stable Disease (SD).

The preliminary anti-tumour activity of AZD1775 (adavosertib) when combined with MEDI4736 (durvalumab) in patients with advanced solid tumours will be determined by the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1.

Overall survival is defined as the time from the date of first dose of study drug until death due to any cause. Any subject known to be alive at the time of analysis will be censored based on the last recorded date on which the subject was known to be alive. Equivalent to PFS, patients will be followed for survival until the last patient has discontinued study drug.

To characterise the effect of AZD1775 (adavosertib) on QTc in patients with advanced solid tumours when combined with MEDI4736 (durvalumab) triplicate ECGs will be obtained at screening and approximately 2-5 minutes apart at the time of PK sample collection as follows: Day -5 pre-dose AZD1775 (adavosertib), Cycle 1 Day 17 pre-dose AZD1775 (adavosertib) and 4 hours post-dose. The ECG assessments will be performed before the PK sample is collected.

Levels of immunologically relevant leukocyte subpopulations will be measured by analysis of a panel of cytokines and chemokines involved in Th1-driven immune responses and changes in proliferating T cells.

Spots Global Cancer Trial Database for azd1775 + medi4736