ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 1 of 21 for:    AZD5363
Previous Study | Return to List | Next Study

Trial of Olaparib in Combination With AZD5363 (ComPAKT) (ComPAKT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02338622
Recruitment Status : Unknown
Verified January 2015 by Royal Marsden NHS Foundation Trust.
Recruitment status was:  Recruiting
First Posted : January 14, 2015
Last Update Posted : January 19, 2015
Sponsor:
Collaborators:
Institute of Cancer Research, United Kingdom
AstraZeneca
Information provided by (Responsible Party):
Royal Marsden NHS Foundation Trust

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).


Condition or disease Intervention/treatment Phase
Advanced Cancer Drug: olaparib Drug: AZD5363 Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 58 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Multi-centre Trial of the Combination of Olaparib (PARP Inhibitor) and AZD5363 (AKT Inhibitor) in Patients With Advanced Solid Tumours
Study Start Date : March 2014
Estimated Primary Completion Date : October 2015
Estimated Study Completion Date : October 2015

Resource links provided by the National Library of Medicine

Drug Information available for: Olaparib

Arm Intervention/treatment
Experimental: Schedule A: 4 days on, 3 days off

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
olaparib BD
Other Name: AZD2281

Drug: AZD5363
AZD5363 BD

Experimental: Schedule B: 2 days on, 5 days off

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
olaparib BD
Other Name: AZD2281

Drug: AZD5363
AZD5363 BD




Primary Outcome Measures :
  1. Safety/tolerability of olaparib in combination with AZD5363 [ Time Frame: 3 to 9 weeks at least. ]
    Dose at which no more than one out of six patient at the same dose level experiences a probable drug-related dose limiting toxicity.

  2. Maximum tolerated dose and recommended Phase II dose of this combination in patients with advanced solid tumours. [ Time Frame: 3 to 9 weeks at least. ]
    Dose at which no more than one out of six patient at the same dose level experiences a probable drug-related dose limiting toxicity.


Secondary Outcome Measures :
  1. Plasma levels of olaparib and AZD5363 using validated assays. [ Time Frame: Average of 2 years ]
    Plasma levels of olaparib and AZD5363 using validated assays.

  2. pAkt/Akt, pGSK/GSK3, pS6 kinase/S6 kinase and pPRAS40/PRAS40 ratios in pre- and post-treatment tumour biopsies using validated assays. [ Time Frame: Average of 2 years ]
    Changes in platelet rich plasma, hair follicles and pre- and post-treatment tumour biopsies using validated assays


Other Outcome Measures:
  1. Exploratory biomarkers [ Time Frame: Average of 2 years ]
    Changes in exploratory biomarkers, including pERK, RAD51, BRCA and PARP expression in pre- and post-treatment tumour biopsies

  2. Putative predictive biomarkers of response and resistance in archival tumours and fresh tumour biopsies [ Time Frame: Average of 2 years ]
    Correlate anti-tumour activity of the combination of olaparib and AZD5363 with the detection of putative predictive biomarkers of response and resistance in archival tumours and fresh tumour biopsies

  3. Disease response by RECIST criteria v1.1 and tumour markers and change in tumour size [ Time Frame: Average of 2 years ]
    Preliminary assessment of the antitumour putative predictive biomarkers of response and resistance to the combination of olaparib and AZD5363.

  4. MTD safely established using an intrapatient dose escalation strategy [ Time Frame: Average of 2 years ]
    Evaluate a novel experimental trial design involving intrapatient dose escalation of AZD5363 in combination with olaparib.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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.

  2. Life expectancy of at least 12 weeks
  3. WHO performance status of 0-1 with no significant deterioration over the previous 2 weeks
  4. Evaluable or measurable disease as assessed by RECIST 1.1
  5. 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

Exclusion Criteria:

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. Major surgery (excluding minor procedures, e.g. placement of vascular access) within 4 weeks of the first dose of study treatment.
  6. 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.
  7. 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.
  8. Proteinuria 3+ on dipstick analysis or >500mg/24 hours.
  9. Previous treatment with a PARP inhibitor or PI3K/AKT inhibitor (Part B: sporadic cancers arm of dose expansion cohort only).
  10. 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).
  11. 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
  12. Any of the following cardiac criteria:

    • Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 consecutive electrocardiograms
    • Any clinically significant abnormalities in rhythm, conduction or morphology of resting ECG
    • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval
    • Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure New York Heart Association [NYHA0 Grade 2
    • Uncontrolled hypotension - Systolic BP <90mmHg and/or diastolic BP <50mmHg
    • LVEF below institutional lower limit of normal.
  13. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of olaparib and AZD5363.
  14. History of hypersensitivity to active or inactive excipients of AZD5363 or olaparib or drugs with a similar chemical structure or class to AZD5363 and olaparib.
  15. Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this Phase I study. Participation in an observational trial would be acceptable.
  16. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.
  17. Patients with myelodysplastic syndrome or acute myeloid leukaemia

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02338622


Contacts
Contact: Alison Turner, PhD +44 (0)20 8661 3752 alison.turner@icr.ac.uk
Contact: Nitharsan Sathiyayogan, MSc +44 (0)20 8722 4302 nitharsan.sathiyayogan@icr.ac.uk

Locations
United Kingdom
Northern Institute for Cancer, Freeman Hospital Recruiting
Newcastle, Newcastle upon Tyne, United Kingdom, NE7 7DN
Contact: Elizabeth R Plummer, MD    +44(0)191 213844    ruth.plummer@newcastle.ac.uk   
Principal Investigator: Elizabeth R Plummer, MD         
Royal Marsden NHS Foundation Trust Recruiting
Sutton, Surrey, United Kingdom, SM2 5PT
Contact: Timothy A Yap, PhD    0208 661 3539    timothy.yap@icr.ac.uk   
Principal Investigator: Timothy A Yap, PhD         
Sponsors and Collaborators
Royal Marsden NHS Foundation Trust
Institute of Cancer Research, United Kingdom
AstraZeneca
Investigators
Principal Investigator: Timothy A Yap, MBBS MRCP PhD The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust

Responsible Party: Royal Marsden NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT02338622     History of Changes
Other Study ID Numbers: CCR4058
2013-004692-13 ( EudraCT Number )
First Posted: January 14, 2015    Key Record Dates
Last Update Posted: January 19, 2015
Last Verified: January 2015

Keywords provided by Royal Marsden NHS Foundation Trust:
olaparib
AZD5363
intrapatient dose escalation
advanced solid tumours

Additional relevant MeSH terms:
Olaparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents