PIPA: Combination of PI3 Kinase Inhibitors and PAlbociclib

Phase 1

• Conditions: Breast Cancer; Advanced Solid Tumours
• Interventions: Drug: Palbociclib + Taselisib / Pictilisib

• Registration Number: NCT02389842
• Lead Sponsor: Royal Marsden NHS Foundation Trust

Brief Summary

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.

Detailed Description

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 Timeline

• Study First Submitted: 2015-03-11
• Study First Submitted QC: 2015-03-16
• Study First Posted: 2015-03-17
• Study Start: 2015-03-25
• Primary Completion: 2018-10-31
• Status Verified: 2019-11
• Last Update Submitted: 2019-11-15
• Last Update Posted: 2019-11-19
• Study Completion: 2020-01

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 93

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Palbociclib + Taselisib	Palbociclib + Taselisib / Pictilisib	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.
Palbociclib + Pictilisib	Palbociclib + Taselisib / 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.

Primary Outcome Measures

Name	Time	Method
Preliminary anti-tumour assessment of triplet combination (RECIST criteria version 1.1) in patients with PIK3CA mutant advanced ER+ve HER2-ve breast cancer.	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.
Safety and Toxicity Profile (National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0)	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
Recommended dose for Phase II	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.

Secondary Outcome Measures

Name	Time	Method
Pharmaockinetics Profile (AUC0-24 and Cmax)	duration of study (24 months)	To determine the plasma levels of the investigational drugs using validated assays: AUC0-24 and Cmax.

Trial Locations

Locations (2)

The Royal Marsden NHS Foundation Trust; 🇬🇧 London, United Kingdom

The Christie NHS Foundation Trust; 🇬🇧 Manchester, United Kingdom