PIPA: Combination of PI3 Kinase Inhibitors and PAlbociclib

NCT02389842 | Completed Phase 1

• 2 other identifiers: CCR41912014-002658-37
• Study Type: interventional
• Target: 79
• Locations: 1 country
• Sites: 2

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.

Conditions

Advanced Solid Tumours; Breast Cancer

Outcome Measures

Primary Outcomes (3)

• Recommended dose for Phase II

  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.

  duration of study (24 months)

• Safety and Toxicity Profile (National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0)

  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

  duration of study (24 months)

• Preliminary anti-tumour assessment of triplet combination (RECIST criteria version 1.1) in patients with PIK3CA mutant advanced ER+ve HER2-ve breast cancer.

  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.

  duration of study (24 months)

Secondary Outcomes (1)

• Pharmaockinetics Profile (AUC0-24 and Cmax)

  duration of study (24 months)

Other Outcomes (4)

• Preliminary anti-tumour assessment (RECIST criteria version 1.1) of combinations.

  duration of study (24 months)

• Mechanisms of Drug Resistance (deep sequence tumour and circulating tumour DNA)

  duration of study (24 months)

• Pharmacodynamics of Pre- and Post-treatment tumour biopsies (biomarker changes)

  duration of study (24 months)

Study Arms (2)

Palbociclib + Taselisib

EXPERIMENTAL

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

Palbociclib + Pictilisib

EXPERIMENTAL

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

Interventions

Palbociclib + Taselisib / Pictilisib DRUG

Palbociclib + Pictilisib; Palbociclib + Taselisib

Eligibility Criteria

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

You may qualify if:

• Part A (dose escalation):
• 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 PIK3CA mutant cancers, or those with somatic mutations or other aberrations known to result in a hyperactivated PI3K-AKT pathway.
• Advanced breast cancer with the following features:
• ER+ve breast cancer that has progressed on at least one line of prior endocrine therapy, or
• PIK3CA mutant breast cancer progressed on at least one line of prior endocrine therapy or chemotherapy
• breast cancer refractory to standard treatment
• Part B (dose expansion):
• Part B1 Patients with histologically or cytologically confirmed advanced ER+ve, HER2-ve breast cancer with a PIK3CA mutation confirmed by an accredited laboratory.
• Part B2
• Patients with histologically or cytologically confirmed advanced solid tumours with mutations leading to a hyperactivated PI3K-AKT pathway, or other relevant genetic aberrations; OR
• Patients with histologically or cytologically confirmed advanced ER-ve, HER2+ve breast cancer with a PIK3CA mutation confirmed by an accredited laboratory; OR
• Patients with histologically or cytologically confirmed advanced triple negative breast cancer with a PIK3CA mutation confirmed by an accredited laboratory.
• Part B3 Patients with histologically or cytologically confirmed advanced ER+ve, HER2-ve breast cancer.
• NB. PIK3CA mutation may be assessed in archival tumour samples, fresh tumour samples, or in circulating free DNA extracted from plasma or serum and the result must be from an accredited laboratory. This is mandatory for breast cancer patients in Part B1 and B2 and the result must be available prior to the patient entering the main study.
• A mutation will be considered pathogenic if described to be recurrent somatic mutation in COSMIC (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/). 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.

You may not qualify if:

• Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous 4 weeks (6 weeks for nitrosoureas, Mitomycin-C) and 4 weeks for investigational medicinal products before treatment
• Exceptions to this are:
• patients progressing on letrozole or fulvestrant;
• hormonal therapy with luteinizing hormone-releasing hormone (LHRH) analogues for medical castration in patients with castrate resistant prostate cancer;
• bisphosphonates or RANK ligand antagonists that are permitted for the management of bone metastases;
• palliative radiotherapy if given for bony metastases, as long as these are not indicative of disease progression. Study drug must be stopped 3 days before radiotherapy and restarted within 28 days, as long as bone marrow function has returned to normal.
• Patients with prior exposure to either a CDK4/6 inhibitor OR a PI3K/ATK/mTOR inhibitor are excluded from the study With the exception of allosteric mTOR inhibitors such as everolimus that is allowed. Prior exposure to fulvestrant or aromatase inhibitors is permitted.
• Clinically significant abnormalities of glucose metabolism as defined by any of the following:
• Diagnosis of diabetes mellitus types I or II (irrespective of management).
• Glycosylated haemoglobin (HbA1C) ≥7.0% at screening
• Fasting Plasma Glucose ≥ 6.9mmol/L at screening. Fasting is defined as no caloric intake for at least 8 hours.
• On-going toxic manifestations of previous treatments ≥ grade 1. Exceptions to this are alopecia or certain other toxicities, which in the opinion of the Investigator should not exclude the patient.
• History of malabsorption syndrome or other condition that would interfere with enteral absorption. For example active intestine inflammation (e.g., Crohn's disease or ulcerative colitis) requiring immunosuppressive therapy.
• History of inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis)
• Inability or unwillingness to swallow pills, or (for patients receiving fulvestrant) receive IM injections.

Sponsors & Collaborators

• Royal Marsden NHS Foundation Trust: lead
• Institute of Cancer Research, United Kingdom: collaborator
• Roche Pharma AG: collaborator
• Pfizer: collaborator

Study Sites (2)

The Royal Marsden NHS Foundation Trust

London, SM2 5PT, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

Location

Related Publications (1)

• Pascual J, Lim JSJ, Macpherson IR, Armstrong AC, Ring A, Okines AFC, Cutts RJ, Herrera-Abreu MT, Garcia-Murillas I, Pearson A, Hrebien S, Gevensleben H, Proszek PZ, Hubank M, Hills M, King J, Parmar M, Prout T, Finneran L, Malia J, Swales KE, Ruddle R, Raynaud FI, Turner A, Hall E, Yap TA, Lopez JS, Turner NC. Triplet Therapy with Palbociclib, Taselisib, and Fulvestrant in PIK3CA-Mutant Breast Cancer and Doublet Palbociclib and Taselisib in Pathway-Mutant Solid Cancers. Cancer Discov. 2021 Jan;11(1):92-107. doi: 10.1158/2159-8290.CD-20-0553. Epub 2020 Sep 21.

  PMID: 32958578 BACKGROUND

MeSH Terms

Conditions

Breast Neoplasms

Interventions

palbociclib; 2-(3-(2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo(f)imidazo(1,2-d)(1,4)oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide; 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Nicholas Turner, PhD

  Institute of Cancer Research, United Kingdom

  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: March 11, 2015
• First Posted: March 17, 2015
• Study Start: March 25, 2015
• Primary Completion: October 31, 2018
• Study Completion: May 26, 2021
• Last Updated: September 26, 2024

Record last verified: 2019-11

Locations

GB (2)