Clinical trial NCT01252628: Phase 1 and 2 Study of PX-866 and Cetuximab
Official title: Phase 1/2 Study of PX-866 and Cetuximab
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Incurable Metastatic Colorectal Carcinoma
Incurable Progressive, Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
Keywords: CRC
SCCHN
PX-866
Cetuximab
ERBITUX
Colon
Head and Neck
Colorectal cancer
Squamous cell carcinoma
PI-3K
PI3 kinase
PI3K
Lead sponsor: Seagen Inc.
Sponsor class: INDUSTRY
First posted: 2010-12-03
Enrollment: 178
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: 21 days
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Birmingham Hematology and Oncology Assocs.
state: Alabama
city: Birmingham
country: United States
facility: University of Alabama Birmingham
state: Alabama
city: Escondido
country: United States
facility: Southwest Cancer Care
state: California
city: Monterey
country: United States
facility: Monterey Bay Oncology
state: California
city: Oxnard
country: United States
facility: Ventura County Hematology Oncology Specialists
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Denver
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Denver
country: United States
facility: Eastern Colorado Health Care System - (Denver VA)
state: Colorado
city: Washington
country: United States
facility: George Washington University - Medical Faculty Associates
state: District of Columbia
city: Jacksonville
country: United States
facility: Integrated Community Oncology Network
state: Florida
city: Miami
country: United States
facility: Advanced Medical Specialties
state: Florida
city: New Port Richey
country: United States
facility: Pasco Pinellas Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Peachtree Hematology-Oncology Consultants
state: Georgia
city: Bethesda
country: United States
facility: Center for Cancer and Blood Disorders
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Bridgeton
country: United States
facility: Saint Louis Cancer Care LLP
state: Missouri
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Tualatin
country: United States
facility: Northwest Cancer Specialists, P.C.
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Charleston
country: United States
facility: MUSC Hollings Cancer Center
state: South Carolina
city: Dallas
country: United States
facility: Mary Crowley Cancer Center
state: Texas
city: Dallas
country: United States
facility: Texas Oncology - Baylor Charles A. Sammons
state: Texas
city: Fort Worth
country: United States
facility: Texas Oncology - Fort Worth
state: Texas
city: Round Rock
country: United States
facility: Texas Oncology - Seton Williamson
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Newport News
country: United States
facility: Peninsula Cancer Institute
state: Virginia
city: Newport News
country: United States
facility: Virginia Oncology Associates
state: Virginia
city: Roanoke
country: United States
facility: Oncology and Hematology Associates of Southwest Virginia
state: Virginia
city: Kennewick
country: United States
facility: Columbia Basin Hematology and Oncology
state: Washington
city: Spokane
country: United States
facility: Medical Oncology Associates
state: Washington
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Vancouver
country: Canada
facility: British Columbia Cancer Agency - Vancouver Centre
state: British Columbia
city: Barrie
country: Canada
facility: Royal Victoria Regional Health Centre
state: Ontario
city: London
country: Canada
facility: London Regional Cancer Program
state: Ontario
city: Sudbury
country: Canada
facility: Northeast Cancer Centre of Health Sciences North
state: Ontario
city: Thunder Bay
country: Canada
facility: Thunder Bay Regional Health Sciences Centre
state: Ontario
city: Greenfield Park
country: Canada
facility: Hôpital Charles-LeMoyne
state: Quebec
city: Laval
country: Canada
facility: Cité de la Santé de Laval
state: Quebec
city: Montreal
country: Canada
facility: Maisonneuve-Rosemont Hospital Research Centre
state: Quebec
Study officials:
affiliation: Cascadian Therapeutics Inc.
name: Diana Hausman, MD
role: STUDY_DIRECTOR
References: