Phase I Study of AZD5363 + Olaparib + Durvalumab in Patients With Advanced or Metastatic Solid Tumor Malignancies

NCT03772561 | Recruiting Phase 1 DMC

• 2 other identifiers: MC01/01/182018/00137
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase 1 dose-escalation study to evaluate the safety and tolerability of combination treatment of AZD5363 + Olaparib + Durvalumab and to determine the RP2D in patients with advanced or metastatic solid tumor malignancies. The purpose of this trial is to determine if combination treatment of drugs, Olaparib, AZD5363 and Durvalumab has beneficial effects in advanced or metastatic cancers and to determine the effects it has on patients and their cancer. Primary Objectives

• To evaluate the safety and tolerability of combination treatment AZD5363 + Olaparib + Durvalumab and determine the Maximum Tolerated Dose (MTD), Dose-Limiting Toxicities (DLTs), and Recommended Phase 2 Dose (RP2D) for patients with advanced or metastatic solid tumor malignancies. Secondary Objectives
• To determine the pharmacodynamics (PDn) of combination treatment AZD5363 + Olaparib + Durvalumab in patients with advanced or metastatic solid tumor malignancies
• To describe anti-tumor response using immune RECIST of combination treatment AZD5363 + Olaparib + Durvalumab in patients with advanced or metastatic solid tumor malignancies Exploratory Objectives
• To evaluate anti-tumour response using RECIST v1.1 for combination treatment AZD5363 + Olaparib + Durvalumab in patients with advanced or metastatic solid tumor malignancies
• To explore molecular correlates of the relationship between mutations in Akt/ PIK3CA/PTEN pathway and response to AZD5363 +Olaparib+ Durvalumab
• To understand the role of tumour microenvironment in regulation of intratumoral immune regulators (i.e. T-regulatory cells) in improving response to Durvalumab
• To understand the role of AZD5363 as an immunomodulator
• To evaluate the role of PD-1 and PDL-1 immunohistochemical and tumour MMR status in predicting response to immune check point inhibitors.

Conditions

Solid Tumor, Adult

Keywords

AZD5363; Olaparib; Durvalumab; Solid Tumor

Outcome Measures

Primary Outcomes (2)

• Objective response rate

  Percentage of patients who have a confirmed visit response of CR or PR.

  5 years

• Best objective response

  Calculated as the best response recorded from date the combination treatment started for each patient.

  5 years

Study Arms (1)

AZD5363+Olaparib+Durvalumab

EXPERIMENTAL

A traditional 3+3 design will be used during the dose escalation part of the study. Patients will receive AZD5363 orally twice a day 4 days-on/ 3 days-off starting 14 days prior to cycle 1 day 1 (C1D1). Olaparib continuously twice a day at 300mg and Durvalumab intravenously at 1500mg once every 4 weeks will commence at C1D1. Treatment will continue until disease progression or the development of unacceptable toxicities.

Drug: AZD5363+Olaparib+Durvalumab

Interventions

AZD5363+Olaparib+Durvalumab DRUG

Patients will receive AZD5363 orally twice a day 4 days-on/ 3 days-off starting 14 days prior to cycle 1 day 1 (C1D1). Olaparib continuously twice a day at 300mg and Durvalumab intravenously at 1500mg once every 4 weeks will commence at C1D1. Treatment will continue until disease progression or the development of unacceptable toxicities.

AZD5363+Olaparib+Durvalumab

Eligibility Criteria

• Age: 21 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All patients must sign an informed consent in accordance with local institutional guidelines.
• Age \>= 21
• Histologically confirmed advanced or metastatic solid tumors who have radiological evidence of progressive disease on study entry and at least 2 measurable lesions, that is deemed unlikely to benefit from further conventional therapy, or for which no standard therapy is available. Although optional, where practicable and safe, all effort should be made by the investigator to obtain serial tumour biopsies from patients enrolled.
• Provision of an archived tumour tissue block (or at least 10 newly cut unstained slides) where such samples exist in a quantity sufficient to allow for analysis
• Any number of prior chemotherapy regimens will be allowed and may include biologics
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1;
• Patients must have adequate bone marrow function and organ function within 2 weeks of study treatment;
• Adequate hematologic function defined as:
• (i) platelets \>= 100 x 109/L in dose escalation phase, (ii) hemoglobin \>= 6.21 mmol/L or 10 g/dL, (iii) ANC \>= 1.5 x 109/L, (iv) WBC \>= 3.0 x 109/L. Up to 5% deviation is tolerated. Transfusions and growth factors are allowed prior to and throughout the study.
• Hepatic function: bilirubin \< 1.5 times the upper limit of normal (ULN), ALT and AST \< 2.5 times ULN. For patients with hepatic metastasis ALT and AST \< 5 times ULN is permitted. Up to 10% deviation is acceptable.
• Adequate renal function: estimated creatinine clearance of \>= 60 mL/min, calculated using the formula of Cockcroft and Gault: (140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply by 0.85 if female.
• Amylase and lipase \<= 1.5 x ULN;
• Alkaline phosphatase limit \<= 2.5 x ULN (\<= 5 x ULN for patients with liver involvement of their cancer);
• International normalization ratio (INR) (if not on anticoagulation therapy) and partial thromboplastin time (PTT) \<= 1.5 x ULN;
• Normal TSH and ACTH

You may not qualify if:

• Patients with significant medical illness that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy;
• Radiation (except planned or ongoing palliative radiation to bone outside of the region of measurable disease) \<= 3 weeks prior to starting first dose of study medication
• Participation in another clinical study with an investigational product (IP) within 30 days of the first dose of AZD5363 or matching placebo.Treatment with any of the following:
• Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment
• Any investigational agents or study drugs from a previous clinical study within 30 days of the first dose of study treatment (\<= 4 weeks for previous PD-1/PD-L1)
• Any other chemotherapy, immunotherapy or anticancer agents within 3 weeks of the first dose of study treatment, except hormonal therapy with LHRH analogues for medical castration in patients with prostate cancer, which are permitted
• Potent inhibitors or inducers or substrates of CYP3A4 or substrates of CYP2D6 within 2 weeks before the first dose of study treatment (3 weeks for St John's Wort )
• Uncontrolled hypertension or controlled hypertension (\<140/90) on more than 3 antihypertensive agents
• Clinically significant abnormalities of glucose metabolism as defined by any of the following:
• o Diabetes mellitus type I
• o Fasting plasma glucose \[fasting is defined as no calorific intake for at least 8 hours\]: (i) \>= 7.0mmol/L (126 mg/dL) for those patients without a pre-existing diagnosis of Type 2 diabetes mellitus (ii) \>= 9.3 mmol/L (167mg/dL) for those patients with a pre-existing diagnosis of Type 2 diabetes mellitus (iii) Glycosylated haemoglobin (HbA1C) \>=8.0% (63.9 mmol/mol). (iv) Requirement for insulin or more than two oral hypoglycaemic medications for routine diabetic management and control
• Major surgical procedure within the last 28 days
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[eg, colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion:
• Subjects with vitiligo or alopecia
• Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement

Sponsors & Collaborators

• National University Hospital, Singapore: lead

Study Sites (1)

National University Hospital

Singapore, Singapore, 119074, Singapore

RECRUITING

Related Publications (2)

• Ibrahim YH, Garcia-Garcia C, Serra V, He L, Torres-Lockhart K, Prat A, Anton P, Cozar P, Guzman M, Grueso J, Rodriguez O, Calvo MT, Aura C, Diez O, Rubio IT, Perez J, Rodon J, Cortes J, Ellisen LW, Scaltriti M, Baselga J. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov. 2012 Nov;2(11):1036-47. doi: 10.1158/2159-8290.CD-11-0348. Epub 2012 Aug 22.

  PMID: 22915752 BACKGROUND

• Yap TA, Sandhu SK, Carden CP, de Bono JS. Poly(ADP-ribose) polymerase (PARP) inhibitors: Exploiting a synthetic lethal strategy in the clinic. CA Cancer J Clin. 2011 Jan-Feb;61(1):31-49. doi: 10.3322/caac.20095. Epub 2011 Jan 4.

  PMID: 21205831 BACKGROUND

Study Officials

• David SP Tan

  National University Hospital, Singapore

  PRINCIPAL INVESTIGATOR

Central Study Contacts

David SP Tan

CONTACT

(65) 6779 5555; david_sp_tan@nuhs.edu.sg

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 10, 2018
• First Posted: December 11, 2018
• Study Start: December 3, 2018
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: July 22, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

SG (1)