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Advanced CancerPhase 1ComPAKTNCT02338622

Trial of Olaparib in Combination With AZD5363 (ComPAKT)

A Phase 1 study testing olaparib and AZD5363 in people with Advanced Cancer, run by Royal Marsden NHS Foundation Trust at 2 sites in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Advanced Cancer
What is being tested?
olaparib and AZD5363
Could I receive a placebo?
No, everyone receives an active treatment
How many people
60 participants
Where
2 sitesUnited Kingdom
Study dates
31 Mar 2014to 21 Mar 2017
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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

Who cannot join

  • 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.
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  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.
  • Patients with myelodysplastic syndrome or acute myeloid leukaemia

Trial locations and contacts

2 sites in 1 country.

United Kingdom2 sites

  • Northern Institute for Cancer, Freeman Hospital

    Newcastle, Newcastle Upon Tyne, NE7 7DN

  • Royal Marsden NHS Foundation Trust

    Sutton, Surrey, SM2 5PT

Other trials in United Kingdom

About this study

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

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.

Read more

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).

Read the detailed description

Part A: The starting doses for both intermittent schedules will be 300 mg bd of olaparib and either AZD5363 given at 320 mg bd 4-days-on, 3-days-off, or 480 mg bd 2-days-on, 5-days-off. These starting doses are based on available data from the first-in-human studies [D0810C00002] (AstraZeneca) and [D3610C00001] (AstraZeneca) of both drugs, respectively.

A general schema for 3 potential dose levels to be pursued on the 4-days-on, 3-days-off AZD5363 schedule (Schedule A) and 2-days-on, 5-days-off AZD5363 schedule (Schedule B) in Part A of the study are listed below. The starting dose of olaparib will be fixed at 300mg bd in both schedules. These schema only provide general guidance; it will be possible for doses of one or both drugs to be escalated or de-escalated in a "seesaw" fashion contingent on the toxicity and/or PK/PD data reported. This may create dose cohort combinations not listed below. Both PK and PD data will be taken into consideration if available. With the exception of dose level 1, actual dose escalation/de-escalation will be determined following a discussion with the SRC during dose escalation teleconferences. Dose escalation will continue until MTD(s) are reached. Patients will be dosed on a flat scale and not by body weight or body surface area. Both schedules will be carried out in parallel.

Table 1: Schema for dose escalation in schedule A (4-days-on, 3-days-off AZD5363) Dose level (DL) olaparib bd AZD5363 bd 4d-on, 3d-off

  • 1 200mg* 240mg
  1. 300mg 320mg
  2. 300mg 400mg
  3. 300mg 480mg *An intermediate dose of 250mg bd of olaparib may be considered depending on drug-related toxicities observed and patient tolerability Table 2: Schema for dose escalation in schedule B (2-days-on, 5-days-off AZD5363) Dose level (DL) olaparib bd AZD5363 bd 2d-on, 5d-off
  • 1 200mg* 400mg
  1. 300mg 480mg
  2. 300mg 560mg
  3. 300mg 640mg
  • An intermediate dose of 250mg bd of olaparib may be considered depending on drug-related toxicities observed and patient tolerability

After careful review of the clinical toxicity data, if the DLT is deemed to be caused by one of the agents, the responsible drug may be dose decreased and if well tolerated, the other agent maybe be increased in subsequent cohorts. If necessary, both drugs can also be dose de-escalated.

In Part A of the study, olaparib will be administered continuously with intermittent AZD5363 in 21-day cycles. Intrapatient dose escalation of AZD5363 will be utilised to evaluate different dose levels. The optimal dose schedule selected based on toxicity, PK-PD and/or efficacy data will be taken forward into two expansion cohorts in Part B of the study. Cohort 1 will comprise patients with germline BRCA1/2 mutated tumours, while Cohort 2 will comprise advanced sporadic cancers that may harbour HR defects (e.g. TNBC, CRPC and HGSOC) or those with somatic mutations or other aberrations known to result in a hyperactivated phosphatidylinositol-3-kinase (PI3K)-AKT pathway.

Conditions
Advanced Cancer
Being tested
olaparib, AZD5363
Keywords
olaparib, AZD5363, intrapatient dose escalation, advanced solid tumours

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • olaparibDrug

    Also called AZD2281

    olaparib BD

  • AZD5363Drug

    AZD5363 BD

Study groups in NCT02338622
Study groupRoleWhat they receive
Schedule A: 4 days on, 3 days offExperimental300mg 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
Receives: Drug: olaparib; Drug: AZD5363
Schedule B: 2 days on, 5 days offExperimental300mg 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
Receives: Drug: olaparib; Drug: AZD5363

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 3 to 9 weeks at least.

  2. 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.

    Measured: 3 to 9 weeks at least.

Secondary outcomes (2)

  1. Plasma levels of olaparib and AZD5363 using validated assays.

    Plasma levels of olaparib and AZD5363 using validated assays.

    Measured: Average of 2 years

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

    Changes in platelet rich plasma, hair follicles and pre- and post-treatment tumour biopsies using validated assays

    Measured: Average of 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Jan 2015 (estimated)
  2. Study start31 Mar 2014
  3. Primary completion21 Mar 2016
  4. Study completion21 Mar 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
60 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02338622
Sponsor's protocol ID
CCR4058
Other IDs
2013-004692-13
Acronym
ComPAKT
Status last verified
Jan 2020
First submitted
3 Jul 2014
Last updated
26 Sep 2024
Results posted
No
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 32532747

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing olaparib and AZD5363 in people with Advanced Cancer, run by Royal Marsden NHS Foundation Trust at 2 sites in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Safety/tolerability of olaparib in combination with AZD5363 (time frame: 3 to 9 weeks at least.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02338622, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Sep 2024.

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