PIPA: Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
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|ClinicalTrials.gov Identifier: NCT02389842|
Recruitment Status : Active, not recruiting
First Posted : March 17, 2015
Last Update Posted : November 19, 2019
Part A: This is a phase Ib trial combining the CDK4/6 inhibitor palbociclib with the PI3K inhibitors taselisib, or pictilisib. There are two treatment arms during the dose escalation phase where patients will receive either taselisib OR pictilisib in combination with palbociclib. Palbociclib, taselisib and pictilisib can all be given orally once daily with food, in a 21-days-on and 7-days-off schedule. Once the MTD is reached, the combination with the optimum safety and PK/PD profile will be taken forward to the dose expansion phase (Part B).
Part B1: At the MTD dose expansion, fulvestrant will be administered in addition to palbociclib and taselisib or pictilisib orally once daily, in a 21-days-on and 7-days-off schedule in the ER+ve HER2-ve PIK3CA mutant breast cancer cohort. Fulvestrant will be given intramuscularly on Day 1, Day 15 in cycle one followed by Day 1 for all subsequent cycles.
Part B2: At the MTD dose expansion, patients with PIK3CA mutant advanced solid tumours will be treated with palbociclib and taselisib or pictilisib orally once daily, in a 21-days-on and 7-days-off schedule.
|Condition or disease||Intervention/treatment||Phase|
|Advanced Solid Tumours Breast Cancer||Drug: Palbociclib + Taselisib / Pictilisib||Phase 1|
This is a phase Ib trial of palbociclib in combination with either taselisib or pictilisib. The study will include a dose escalation phase (Part A), and an MTD dose expansion phase (Part B).
Part A: will investigate escalating doses of palbociclib with either pictilisib or taselisib administered orally, continuously for 21 days out of a 28 day cycle in patients with advanced solid tumours recruited simultaneously into two parallel arms (up to 24 patients in each arm with a maximum of 48 patients in Part A).
Once the MTD is determined the combination with the optimum safety and PK/PD profile as determined by the SRC will be taken forward to the dose expansion phase (Part B).
Part B: The MTD dose expansion phase will be conducted using the optimal combination from Part A in two parallel arms as follows:
B1: Patients (n=25) with PIK3CA mutant ER + HER2-ve advanced breast cancers will be treated with a triplet combination of palbociclib and either taselisib or pictilisib along with fulvestrant. Part B1 will require at least two of the first 15 patients to respond to progress to recruit the full 25 patients.
B2: Patients (n=20) with PIK3CA mutant advanced solid tumours including at least 8 patients with PIK3CA mutant ER negative and/or HER2 positive breast cancers will be treated with the doublet combination of palbociclib and either taselisib or pictilisib. Other cancers with relevant genetic aberrations (e.g. KRAS mutations) may be considered, depending on emerging preclinical and clinical data on these novel antitumour agents.
In total, it is expected that a minimum of 70 and up to a maximum of 93 patients will be enrolled into the trial, the final number will depend on the number of dose escalations required to reach DLT. If < 48 patients are enrolled in Part A, investigators will be permitted to enrol > 45 patients in Part B, providing the maximum number of patients remains ≤93 patients across the study.
The anticipated accrual rate during the dose escalation phase is estimated at 2 patients per month. Accrual in the expansion phase is estimated at 4 patients per month across 2 centres. It is expected that the trial will have a duration of recruitment of 12 to 24 months.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||93 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||PIPA: A Phase Ib Study to Assess the Safety, Tolerability and Efficacy of the PI3K Inhibitors, Taselisib (GDC-0032) or Pictilisib (GDC-0941), in Combination With PAlbociclib, With the Subsequent Addition of Fulvestrant in PIK3CA-mutant Breast Cancers|
|Actual Study Start Date :||March 25, 2015|
|Actual Primary Completion Date :||October 31, 2018|
|Estimated Study Completion Date :||January 2020|
Experimental: Palbociclib + Taselisib
The starting dose of palbociclib in combination with taselisib will be 100mg OD of palbociclib and 2mg taselisib OD, administered orally 21-days-on and 7-days-off, as part of a 28 day cycle.
Drug: Palbociclib + Taselisib / Pictilisib
Experimental: Palbociclib + Pictilisib
The starting dose of palbociclib in combination with pictilisib will be 100mg OD of palbociclib and 195 mg pictilisib OD, administered orally 21-days-on and 7-days-off, as part of a 28 day cycle.
Drug: Palbociclib + Taselisib / Pictilisib
- Recommended dose for Phase II [ Time Frame: duration of study (24 months) ]To determine a dose at which no more than one patient out of up to six patients at the same dose level experience a highly probable or probable drug-related dose limiting toxicity.
- Safety and Toxicity Profile (National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) [ Time Frame: duration of study (24 months) ]To evaluate causality of each adverse event to palbociclib with taselisib and fulvestrant; palbociclib and taselisib; letrozole, palbociclib and taselisib against CTCAE criteria V4.0
- Preliminary anti-tumour assessment of triplet combination (RECIST criteria version 1.1) in patients with PIK3CA mutant advanced ER+ve HER2-ve breast cancer. [ Time Frame: duration of study (24 months) ]To evaluate disease response by RECIST criteria version 1.1, clinical benefit rate, best change in tumour size, progression free survival, and duration or response.
- Pharmaockinetics Profile (AUC0-24 and Cmax) [ Time Frame: duration of study (24 months) ]To determine the plasma levels of the investigational drugs using validated assays: AUC0-24 and Cmax.
- Preliminary anti-tumour assessment (RECIST criteria version 1.1) of combinations. [ Time Frame: duration of study (24 months) ]To evaluate disease response by RECIST criteria version 1.1, clinical benefit rate, best change in tumour size, progression free survival, and duration or response.
- Mechanisms of Drug Resistance (deep sequence tumour and circulating tumour DNA) [ Time Frame: duration of study (24 months) ]To deep sequence tumour and circulating tumour DNA at baseline, during treatment and on progression.
- Pharmacodynamics of Pre- and Post-treatment tumour biopsies (biomarker changes) [ Time Frame: duration of study (24 months) ]To determine biomarker changes, including: phospho (e.g. pRbser780) and total retinoblastoma protein (Rb), phospho (pSer473) and total AKT, phospho (pThr246) and total PRAS40, Ki67 and TUNEL.
- Pharmacodynamics Profile using PRP (biomarker changes) [ Time Frame: duration of study (24 months) ]To determine PD biomarker changes, such as: phospho and total AKT, GSK3b, pS70S6K and PRAS40 using the validated MSD electrochemiluminescent triplex platform.
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): NCT02389842
|The Royal Marsden NHS Foundation Trust|
|London, United Kingdom, SM2 5PT|
|The Christie NHS Foundation Trust|
|Manchester, United Kingdom, M20 4BX|
|Principal Investigator:||Nicholas Turner, PhD||Institute of Cancer Research, United Kingdom|