Phase 1 and 2 Study of PX-866 and Cetuximab

Phase 1

Completed

Conditions: Incurable Progressive, Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
Incurable Metastatic Colorectal Carcinoma

Interventions: Drug: Cetuximab (CRC)
Drug: PX-866 (SCCHN)
Drug: Cetuximab (SCCHN)
Drug: PX-866 (CRC)

Registration Number: NCT01252628

Lead Sponsor: Cascadian Therapeutics Inc.

Brief Summary: The purpose of this Phase 1/2 open-label study is to determine the safety and efficacy of a cetuximab and PX-866 combination treatment. In the Phase 1 part of the study, the dose of PX-866 to be given in combination with cetuximab will be determined in patients with incurable metastatic CRC or incurable progressive, recurrent or metastatic SCCHN. The Phase 2 part of the study is a randomized evaluation of the antitumor activity and safety of PX-866 in combination with cetuximab versus cetuximab alone in patients with either incurable metastatic CRC who have a history of progression or recurrence following prior irinotecan and oxaliplatin containing regimens or are intolerant of irinotecan (Group 1) or incurable progressive, recurrent or metastatic SCCHN (Group 2).

Detailed Description: Phase 1 will determine the maximally tolerated or recommended dose of PX-866 to be given orally on Days 1-21 in combination with cetuximab 250 mg/m2 administered IV weekly on Days 1, 8, and 15 of a 21-day cycle. All patients will receive an initial loading dose of 400 mg/m2 cetuximab rather than 250 mg/m2 on Cycle 1 Day 1. Patients may receive premedication with an H1 antagonist per the cetuximab package insert. Up to 3 dose levels of PX-866 will be evaluated to determine the MTD/RD in cohorts of up to 6 patients using a standard 3+3 dose-escalation design. At least 6 patients will be treated at the MTD/RD. All patients in Phase 1 will be required to undergo PK assessments during Cycle 1 Week 3 to measure cetuximab levels. Exploratory PD assessments will include evaluation of changes in levels of fasting C-peptide as well as changes in EGFR and PI-3K signaling pathways in peripheral blood mononuclear cells (PBMC) and platelets. Additional optional evaluations will include changes in EGFR and PI-3K signaling in paired tumor biopsies provided before and after one cycle of treatment. All patients will be asked, but not required, to provide an archived tumor biopsy sample for evaluation for potential biomarkers of response to PX-866 and cetuximab.

Phase 2 is an open-label, randomized evaluation of the antitumor activity and safety of PX-866 administered orally or via PEG tube (if applicable) at the MTD/RD in combination with cetuximab, versus cetuximab alone in cetuximab-naïve patients with incurable metastatic CRC who have a history of progression or recurrence following prior irinotecan and oxaliplatin containing regimens or are intolerant of irinotecan (Group 1) or patients with incurable progressive, recurrent or metastatic SCCHN (Group 2). Seventy two evaluable patients (36 patients per arm) will be evaluated per indication. Patients will be randomized 1:1 to receive PX-866 + cetuximab or cetuximab alone.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 178

Inclusion Criteria

At least 18 years at time of consent
Use of a medically accepted form of contraception from the time of consent to completion of all follow-up study visits
If female of child-bearing potential, negative pregnancy test
Signed an informed consent
Measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST)
Documentation available for last prior systemic treatment including dates of treatment, best response to treatment, duration of best response, and reason for discontinuation of treatment
Eastern Cooperative Oncology Group (ECOG) 0 or 1
Group 1: Patients with incurable metastatic CRC with a history of progression or recurrence following prior irinotecan and oxaliplatin containing regimens. Patients who have a history of intolerance of irinotecan based therapy or ineligibility to receive irinotecan are also eligible as long as they have received a prior oxaliplatin containing regimen.
Group 2: Patients with incurable SCCHN with a history of progression or recurrence following at least one prior platinum based chemotherapy or chemotherapy/radiation containing regimen. Patients who have a history of intolerance of platinum based therapy or history of ineligibility to receive a platinum based regimen are also eligible. SCCHN patients who received cetuximab as a radiosensitizer for locally advanced disease and completed treatment at least 6 months prior to start of study drug treatment are eligible
In the opinion of the clinical investigator, life expectancy of greater than 3 months
Adequate hematologic function
Adequate hepatic function
Creatinine level ≤1.5 x ULN
Serum magnesium ≥ LLN.

Exclusion Criteria

Has medical, social, or psychosocial factors that, in the opinion of the investigator, could impact safety or compliance with study procedures
Is breastfeeding
Treatment with any systemic chemotherapy, epidermal growth factor receptor (EGFR) inhibitor, radiation or experimental agent within 4 weeks of study drug dosing
Received prior cetuximab, except as defined in inclusion criteria
Previous treatment with a phosphatidylinositol 3-kinase (PI-3K) inhibitor
Known human immunodeficiency virus (HIV)
Poorly controlled diabetes mellitus (IFCC-HbA1C ≥ 53 mmol/mol or DCCT -HbA1C ≥ 7%)
Kras mutation in codon 12 or 13 (CRC patients only)
Known or suspected clinically active brain metastases. Previously treated and stable brain metastases are allowable. Stable brain metastases are defined as no change on CT scan or MRI for minimum of two months AND no change in steroid dose for a minimum of four weeks, unless change due to intercurrent infection or other acute event)
Any other significant medical or psychiatric condition that in the opinion of the investigator renders the patient inadequate for participation
History of severe hypersensitivity to cetuximab

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cetuximab (CRC)	Cetuximab (CRC)	Phase 2 (Colorectal Carcinoma)
PX-866 (SCCHN)	PX-866 (SCCHN)	Phase 2 (Squamous Cell Carcinoma of the Head and Neck)
Cetuximab (SCCHN)	Cetuximab (SCCHN)	Phase 2 (Squamous Cell Carcinoma of the Head and Neck)
PX-866 (SCCHN)	Cetuximab (SCCHN)	Phase 2 (Squamous Cell Carcinoma of the Head and Neck)
PX-866 (CRC)	Cetuximab (CRC)	Phase 2 (Colorectal Carcinoma)
PX-866 (CRC)	PX-866 (CRC)	Phase 2 (Colorectal Carcinoma)

Primary Outcome Measures

Name	Time	Method
The evaluation of antitumor effects of PX-866 in combination with cetuximab versus cetuximab in patients with incurable metastatic colorectal cancer and/or patients with incurable progressive, recurrent or metastatic SCC of the head and neck.	21 days

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (40): Southwest Cancer Care
🇺🇸
Escondido, California, United States
Monterey Bay Oncology
🇺🇸
Monterey, California, United States
Maisonneuve-Rosemont Hospital Research Centre
🇨🇦
Montreal, Quebec, Canada
George Washington University - Medical Faculty Associates
🇺🇸
Washington, District of Columbia, United States
Integrated Community Oncology Network
🇺🇸
Jacksonville, Florida, United States
Northwest Cancer Specialists, P.C.
🇺🇸
Tualatin, Oregon, United States
Medical Oncology Associates
🇺🇸
Spokane, Washington, United States
British Columbia Cancer Agency - Vancouver Centre
🇨🇦
Vancouver, British Columbia, Canada
Thunder Bay Regional Health Sciences Centre
🇨🇦
Thunder Bay, Ontario, Canada
Royal Victoria Regional Health Centre
🇨🇦
Barrie, Ontario, Canada
Hôpital Charles-LeMoyne
🇨🇦
Greenfield Park, Quebec, Canada
Virginia Oncology Associates
🇺🇸
Newport News, Virginia, United States
Ventura County Hematology Oncology Specialists
🇺🇸
Oxnard, California, United States
Saint Louis Cancer Care LLP
🇺🇸
Bridgeton, Missouri, United States
Pasco Pinellas Cancer Center
🇺🇸
New Port Richey, Florida, United States
Texas Oncology - Fort Worth
🇺🇸
Fort Worth, Texas, United States
Cité de la Santé de Laval
🇨🇦
Laval, Quebec, Canada
Peninsula Cancer Institute
🇺🇸
Newport News, Virginia, United States
Columbia Basin Hematology and Oncology
🇺🇸
Kennewick, Washington, United States
London Regional Cancer Program
🇨🇦
London, Ontario, Canada
Cross Cancer Institute
🇨🇦
Edmonton, Alberta, Canada
Oncology and Hematology Associates of Southwest Virginia
🇺🇸
Roanoke, Virginia, United States
Northeast Cancer Centre of Health Sciences North
🇨🇦
Sudbury, Ontario, Canada
University of Colorado Denver
🇺🇸
Aurora, Colorado, United States
Rocky Mountain Cancer Centers
🇺🇸
Denver, Colorado, United States
Peachtree Hematology-Oncology Consultants
🇺🇸
Atlanta, Georgia, United States
Eastern Colorado Health Care System - (Denver VA)
🇺🇸
Denver, Colorado, United States
Virginia Cancer Specialists, PC
🇺🇸
Fairfax, Virginia, United States
Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
Comprehensive Cancer Centers of Nevada
🇺🇸
Las Vegas, Nevada, United States
University of Pennsylvania
🇺🇸
Philadelphia, Pennsylvania, United States
Texas Oncology - Seton Williamson
🇺🇸
Round Rock, Texas, United States
Tufts Medical Center
🇺🇸
Boston, Massachusetts, United States
Texas Oncology - Baylor Charles A. Sammons
🇺🇸
Dallas, Texas, United States
Birmingham Hematology and Oncology Assocs.
🇺🇸
Birmingham, Alabama, United States
University of Alabama Birmingham
🇺🇸
Birmingham, Alabama, United States
Advanced Medical Specialties
🇺🇸
Miami, Florida, United States
Center for Cancer and Blood Disorders
🇺🇸
Bethesda, Maryland, United States
MUSC Hollings Cancer Center
🇺🇸
Charleston, South Carolina, United States
Mary Crowley Cancer Center
🇺🇸
Dallas, Texas, United States