Safety Study of the Combination of Panitumumab, Irinotecan and Everolimus in the Treatment of Advanced Colorectal Cancer (PIE)

A Phase IB/II Study of Second Line Therapy With Panitumumab, Irinotecan and Everolimus (PIE) in Metastatic Colorectal Cancer With KRAS WT

This study will assess the safety of panitumumab, irinotecan and everolimus when given in combination to treat advanced colorectal cancer

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer; Colorectal Tumors; Colorectal Carcinoma; Neoplasms, Colorectal
• Intervention / Treatment: Drug: Panitumumab; Drug: Irinotecan; Drug: Everolimus

Detailed Description

This is an open label uncontrolled phase IB/II study to determine the maximum tolerated dose (MTD) and assess the efficacy of everolimus, irinotecan and panitumumab when given in combination for patients with metastatic colorectal cancer and KRAS wild-type (WT). Patients with metastatic colorectal cancer (mCRC) that have failed fluorouracil based first line therapy will be included. It is anticipated that approximately 50 patients will be enrolled over a period of 24 months

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • South Australia
    • Adelaide, South Australia, Australia, 5011
      • The Queen Elizabeth Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age > 18 years
• Histological diagnosis of colorectal cancer that is KRAS wild type
• Metastatic disease not amenable to resection
• Measurable disease as assessed by CT scan using RECIST criteria
• Received and failed fluoropyrimidine therapy
• Radiographically documented disease progression per RECIST criteria
• For phase 1b group only, ECOG PS 0-1
• For phase 2 group only, ECOG PS 0-2
• Adequate bone marrow function with haemoglobin > 100 g/L, platelets > 100 X 109/l; neutrophils > 1.5 X 109/l within 7 days of enrolment
• Adequate renal function, with calculated creatinine clearance >40 ml/min (Cockcroft and Gault) within 7 days of enrolment
• Adequate hepatic function with serum total bilirubin < 1.25 X upper limit of normal range and ALT or AST<2.5xULN (<5xULN if liver metastases present) within 7 days of enrolment
• Magnesium ≥ lower limit of normal within 7 days of enrolment.
• Fasting serum cholesterol ≤ 7.75mmol/L AND fasting triglycerides ≤ 2.5 x ULN. Note: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication.
• Life expectancy of at least 12 weeks
• Negative pregnancy test ≤ 72 hours before commencing study treatment (women of childbearing potential only).
• Written informed consent including consent for biomarker studies

Exclusion Criteria:

• Presence of KRAS mutation in tumour sample
• For Phase 1b group only, patients with prior pelvic radiotherapy.
• Systemic chemotherapy, immunotherapy, approved proteins/antibodies or any investigational agent within 4 weeks prior to commencing study treatment
• Radiotherapy within 14 days of commencing study treatment.
• Unresolved toxicities from prior systemic therapy or radiotherapy
• Medical or psychiatric conditions that compromise the patient's ability to give informed consent or to complete the protocol
• Prior treatment with drugs targeting EGFR such as cetuximab, panitumumab or erlotinib
• Prior therapy with mTOR inhibitors (sirolimus, temsirolimus, everolimus)
• Prior therapy with irinotecan
• CYP3A4 enzyme inducing anti-convulsant medication ≤ 14 days prior to study treatment.
• Ketoconazole ≤ 7 days before study treatment.
• Uncontrolled diabetes mellitus defined by fasting glucose >1.5 x ULN.
• Known cirrhosis, chronic active hepatitis, or chronic persistent hepatitis
• Patients with known interstitial lung disease or severely impaired lung function
• Patients with active bleeding diatheses.
• Any uncontrolled clinically significant cardiac disease, arrhythmias or angina pectoris
• Active inflammatory bowel disease or other bowel disease causing chronic diarrhoea
• Chronic treatment with immunosuppressives
• Patients with a known history of HIV seropositivity
• Patients who have any severe and/or uncontrolled medical conditions or infections
• Untreated or symptomatic CNS metastases
• Patients who have a history of another primary malignant disease
• Pregnancy or lactation.
• Women and partners of women of childbearing potential who are not using effective contraception.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Panitumumab + Irinotecan + Everolimus	Drug: Panitumumab; Panitumumab 6mg/kg IV every 14 days; Other Names: Vectibix; Drug: Irinotecan; Irinotecan 200mg/m2 IV every 14 days; Drug: Everolimus; Everolimus daily po (dosage varies with cohort); Other Names: RAD001

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose limiting toxicities	To determine the maximum tolerated dose (MTD)of everolimus, irinotecan and panitumumab when given in combination for patients with Kras WT mCRC	at end of cycle 2 (each cycle is 14 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety & toxicity	Safety and toxicity assessed weekly during the phase Ib component (as per NCI CTCAE version 3.0) and fortnightly during the phase II component	Approximately 24 weeks
Response rate	Objective tumour response as per RECIST criteria V1.0	Assessed every 6 weeks until disease progression
Progression free survival		Until disease progression, occurrence of new disease or death
Overall Survival		Assessed 3 monthly until death

Collaborators and Investigators

• Sponsor: The Queen Elizabeth Hospital
• Collaborators: Novartis; Amgen
• Investigators: Principal Investigator: Amanda Townsend, MBBS, The Queen Elizabeth Hospital

Study record dates

Study Major Dates

• Study Start: June 1, 2010
• Primary Completion (Actual): August 1, 2015
• Study Completion (Actual): June 1, 2017

Study Registration Dates

• First Submitted: May 28, 2010
• First Submitted That Met QC Criteria: June 7, 2010
• First Posted (Estimate): June 8, 2010

Study Record Updates

• Last Update Posted (Actual): November 6, 2017
• Last Update Submitted That Met QC Criteria: November 2, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: Colorectal Cancer; Colorectal Carcinoma; Colorectal Tumors; Neoplasms, Colorectal
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Topoisomerase I Inhibitors; Irinotecan; Panitumumab; Everolimus
• Other Study ID Numbers: AU-2009-0003/CRAD001CAU06T