Trial of Olaparib in Combination with AZD5363 (ComPAKT)

NCT02338622 | Completed Phase 1 DMC

• 2 other identifiers: CCR40582013-004692-13
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 2

Brief Summary

This is a phase I trial of the combination of the PARP inhibitor olaparib and AKT inhibitor AZD5363. There are two parts to this study. Part A: dose escalation, and Part B: dose expansion. Part A will investigate the combination of 300 mg bd of olaparib with intrapatient ascending doses of AZD5363 administered for either 4-days-on, 3-days-off, and 2-days-on, 5-days-off. Once the Maximum Tolerated Dose (MTD) is reached for both arms (or under the advice from the Safety Review Committee (SRC) one of the schedules will be discontinued), the schedule with the optimum safety and PK/PD profile will be taken forward to a dose expansion phase (Part B). Part B will evaluate the optimized dose/schedule identified in Part A of the study in patients with (1) BRCA1/2 mutant cancers (with previous disease progression on PARP inhibitor monotherapy), or (2) advanced sporadic tumours (e.g. TNBC, CRPC, HGSOC and tumours with somatic mutations or other aberrations known to result in a hyperactivated PI3K-AKT pathway).

Conditions

Advanced Cancer

Keywords

olaparib; AZD5363; intrapatient dose escalation; advanced solid tumours

Outcome Measures

Primary Outcomes (2)

• Safety/tolerability of olaparib in combination with AZD5363

  Dose at which no more than one out of six patient at the same dose level experiences a probable drug-related dose limiting toxicity.

  3 to 9 weeks at least.

• Maximum tolerated dose and recommended Phase II dose of this combination in patients with advanced solid tumours.

  Dose at which no more than one out of six patient at the same dose level experiences a probable drug-related dose limiting toxicity.

  3 to 9 weeks at least.

Secondary Outcomes (2)

• Plasma levels of olaparib and AZD5363 using validated assays.

  Average of 2 years

• pAkt/Akt, pGSK/GSK3, pS6 kinase/S6 kinase and pPRAS40/PRAS40 ratios in pre- and post-treatment tumour biopsies using validated assays.

  Average of 2 years

Other Outcomes (4)

• Exploratory biomarkers

  Average of 2 years

• Putative predictive biomarkers of response and resistance in archival tumours and fresh tumour biopsies

  Average of 2 years

• Disease response by RECIST criteria v1.1 and tumour markers and change in tumour size

  Average of 2 years

Study Arms (2)

Schedule A: 4 days on, 3 days off

EXPERIMENTAL

300mg olaparib + intrapatient dose escalation of AZD5363 4 days on, 3 days off Schema for dose escalation in schedule A (4-days-on, 3-days-off AZD5363) -1. Olaparib: 200mg, AZD5363 240mg 1. Olaparib: 300mg, AZD5363 320mg 2. Olaparib: 300mg, AZD5363 400mg 3. Olaparib: 300mg, AZD5363 480mg

Drug: olaparib; Drug: AZD5363

Schedule B: 2 days on, 5 days off

EXPERIMENTAL

300mg olaparib + intrapatient dose escalation of AZD5363 2 days on, 5 days off Schema for dose escalation in schedule B (2-days-on, 5-days-off AZD5363) -1. Olaparib: 200mg, AZD5363 400mg 1. Olaparib: 300mg, AZD5363 480mg 2. Olaparib: 300mg, AZD5363 560mg 3. Olaparib: 300mg, AZD5363 640mg

Drug: olaparib; Drug: AZD5363

Interventions

olaparib DRUG

olaparib BD

Also known as: AZD2281

Schedule A: 4 days on, 3 days off; Schedule B: 2 days on, 5 days off

AZD5363 DRUG

AZD5363 BD

Schedule A: 4 days on, 3 days off; Schedule B: 2 days on, 5 days off

Eligibility Criteria

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

You may qualify if:

• Part A: Patients with histologically or cytologically confirmed malignant advanced solid tumours refractory to standard therapy or for which no suitable effective standard therapy exists, including, but not limited to patients with: BRCA1/2 mutant cancers, TNBC, CRPC and HGSOC, and those with somatic mutations or other aberrations known to result in a hyperactivated PI3K-AKT pathway.
• Part B: (1) BRCA1/2 mutation cohort: Patients with advanced germline BRCA1/2 mutant solid tumours; (2) Sporadic cancers cohort: This cohort will include advanced sporadic cancers that are not known to harbour germline BRCA1/2 mutations, but which may harbour homologous recombination (HR) defects, e.g. advanced TNBC, CRPC and HGSOC, and those with somatic mutations or other aberrations known to result in a hyperactivated PI3K-AKT pathway.
• Life expectancy of at least 12 weeks
• WHO performance status of 0-1 with no significant deterioration over the previous 2 weeks
• Evaluable or measurable disease as assessed by RECIST 1.1
• Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week.
• Hb ≥ 10.0 g/dL
• Absolute neutrophil count ≥ 1.5 x 109/L
• Platelet count ≥ 100 x 109/L
• Serum bilirubin ≤ 1.5 x upper limit of normal except for patient with documented Gilburt's disease
• ALT or AST ≤ 2.5 x (ULN) unless raised due to tumour in which case up to 5 times ULN is permissible
• If creatinine \> 1.5 times ULN then: Either:
• Creatinine Clearance ≥ 50 mL/min (uncorrected value)
• Isotope clearance measurement ≥ 50 mL/min (corrected) 6.18 years or over 7. Signed and dated informed consent and be capable of co-operating with treatment and follow-up

You may not qualify if:

• Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C) and 4 weeks for investigational medicinal products before treatment, except for hormonal therapy with luteinizing hormone-releasing hormone analogues for medical castration in patients with CRPC, which are permitted.
• Ongoing toxic manifestations of previous treatments. Exceptions to this are Grade 1 toxicities, which in the opinion of the Investigator should not exclude the patient.
• Ability to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum or urine pregnancy test before enrolment and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom, have an intra-uterine device and condom, diaphragm with spermicidal gel and condom) for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible.
• Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using one form of highly effective contraception \[condom plus spermicide\] during the trial and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (for example, condom plus spermicidal gel) to prevent exposure to the foetus or neonate.
• Major surgery (excluding minor procedures, e.g. placement of vascular access) within 4 weeks of the first dose of study treatment.
• At high medical risk because of severe or uncontrolled systemic disease including active bleeding diathesis or active infection including hepatitis B, hepatitis C and human immunodeficiency virus. Screening for chronic conditions is not required.
• Clinically significant abnormalities of glucose metabolism as defined by any of the following:
• Diagnosis of diabetes mellitus type I or II (irrespective of management).
• HbA1C ≥ 8.0% at screening (64 mmol/mol) (conversion equation for HbA1C \[IFCC-HbA1C (mmol/mol)\] = \[DCCT-HbA1C (%) - 2.15\] x 10.929)
• Fasting Plasma Glucose ≥ 8.9mmol/L at screening. Fasting is defined as no caloric intake for at least 8 hours.
• Proteinuria 3+ on dipstick analysis or \>500mg/24 hours.
• Previous treatment with a PARP inhibitor or PI3K/AKT inhibitor (Part B: sporadic cancers arm of dose expansion cohort only).
• Treatment with 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).
• Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatment
• Any of the following cardiac criteria:

Sponsors & Collaborators

• Royal Marsden NHS Foundation Trust: lead
• Institute of Cancer Research, United Kingdom: collaborator
• AstraZeneca: collaborator

Study Sites (2)

Northern Institute for Cancer, Freeman Hospital

Newcastle, Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Royal Marsden NHS Foundation Trust

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Related Publications (1)

• Yap TA, Kristeleit R, Michalarea V, Pettitt SJ, Lim JSJ, Carreira S, Roda D, Miller R, Riisnaes R, Miranda S, Figueiredo I, Rodrigues DN, Ward S, Matthews R, Parmar M, Turner A, Tunariu N, Chopra N, Gevensleben H, Turner NC, Ruddle R, Raynaud FI, Decordova S, Swales KE, Finneran L, Hall E, Rugman P, Lindemann JPO, Foxley A, Lord CJ, Banerji U, Plummer R, Basu B, Lopez JS, Drew Y, de Bono JS. Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with BRCA1/2- and Non-BRCA1/2-Mutant Cancers. Cancer Discov. 2020 Oct;10(10):1528-1543. doi: 10.1158/2159-8290.CD-20-0163. Epub 2020 Jun 12.

  PMID: 32532747 BACKGROUND

MeSH Terms

Interventions

olaparib; capivasertib

Study Officials

• Timothy A Yap, MBBS MRCP PhD

  The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: July 3, 2014
• First Posted: January 14, 2015
• Study Start: March 31, 2014
• Primary Completion: March 21, 2016
• Study Completion: March 21, 2017
• Last Updated: September 26, 2024

Record last verified: 2020-01

Locations

GB (2)