Study to assess safety and tolerability of PF-05212384 in combination with other anti-tumor agents

• Register: EUCTR
• Last refreshed on: 9 May 2016
• Main ID: EUCTR2013-002095-40-ES
• Date of registration: 11/03/2014
• Prospective Registration: Yes
• Primary sponsor: Pfizer Inc.,235 East 42nd Street, New York, NY 10017
• Public title: Study to assess safety and tolerability of PF-05212384 in combination with other anti-tumor agents
• Scientific title: A RANDOMIZED PHASE 2 STUDY OF PF-05212384 PLUS IRINOTECAN VERSUS CETUXIMAB PLUS IRINOTECAN IN PATIENTS WITH KRAS AND NRAS WILD TYPE METASTATIC COLORECTAL CANCER
• Date of first enrolment: 23/04/2014
• Target sample size: 150
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-002095-40
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: yes Other trial design description: 2 independent arms: PF-05212384 + irinotecan (arm A), cetuximab + irinotecan (arm B) If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, France, Germany, Italy, Japan, Korea, Republic of, Poland, Spain, United States

Contacts

• Name: Clinical Trials.gov Call Center
• Affiliation: Pfizer Inc

• Name: Clinical Trials.gov Call Center
• Affiliation: Pfizer Inc

Key inclusion & exclusion criteria

Inclusion criteria:
1. Men or women >=18 years of age (or >=20 years of age if required by local regulation).
2. Patients with histologically confirmed diagnosis of colorectal cancer.
3. RAS (KRAS and NRAS) wild type colorectal cancer. RAS (KRAS and NRAS) wild type status must be known prior to randomization. If results are available from local testing performed prior to entry into this study, they may be used as documentation of RAS (KRAS and NRAS) wild type status, as long as the test was performed using an acceptable test method (approved by the local regulatory health authority in the country in which the patient is enrolled for KRAS). If RAS mutation status is unavailable, then RAS (KRAS and NRAS) testing must be done locally (using an acceptable test method) or by the central vendor during screening, using an archived or fresh biopsy. Patients enrolled in the Japanese lead in cohort may be KRAS wild type only.
4. Availability of archival tumor biopsy specimens, either formalin-fixed paraffin-embedded (FFPE) tumor tissue block or 20 unstained slides, for KRAS and NRAS and other biomarker analysis. Patients will need to provide a fresh biopsy for FFPE if archival material is not available.
5. The first 25 patients in each arm of the study must be willing to provide matched fresh tumor biopsies (if clinically feasible [see Section 7.2 of protocol]) for pharmacodynamic biomarker studies.
6. Documented progression of colorectal cancer following treatment with irinotecan, oxaliplatin, and fluoropyrimidine therapy in the metastatic setting.
7. At least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, V 1.1. Lesion must not have been previously irradiated.
8.Eastern Cooperative Oncology Group (ECOG) status of 0, 1 or 2 (not declining within 2 weeks prior to signing of informed consent); see Appendix 2 of protocol.
9. Adequate bone marrow function as defined by:
-Absolute neutrophil count (ANC) ?1500/mm3 or ?1.5 x 109/L;
-Platelets ?100 x 109/L; and
-Hemoglobin ?9 g/dL.
10. Adequate renal function as defined by:
-Serum creatinine ?1.5 x upper limit of normal (ULN) or
-Estimated creatinine clearance ? 60 ml/min per institutional standard method of calculation
11.Adequate hepatic function as defined by:
-Total serum bilirubin ? 1.5 mg/dL;
-Aspartate and alanine aminotransferase ?2.5 x ULN (? 5.0x ULN in presence of hepatic metastases); and
-Alkaline phosphatase ? 2.5 x ULN (?5.0x ULN in presence of bone metastases).
12.Adequate blood glucose control as defined by:
-Fasting blood glucose ?126 mg/dL; and
-HbA1c <7%.
13. Adequate cardiac functioning as defined by:
-12-Lead electrocardiogram (ECG) with normal tracing or clinically insignificant changes that do not require medical intervention; and
-Patients with QTc interval <480 msec and no known history of QT/QTc prolongation.
14. Resolved acute effects of any prior therapy to baseline severity or Grade ?1 CTCAE except for AEs not constituting a safety risk according to the Investigator?s judgement.
15. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legal representative) has been informed of all pertinent aspects of the study.
16. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
17. Male and female patients of childbearing potential must agree to use 2 highly effective method of contraception throughout the study and for
Exclusion criteria:
1. Patients who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or patients who are Pfizer employees directly involved in the conduct of the trial.
2. More than 2 prior cytotoxic chemotherapy regimens for colorectal cancer in the metastatic setting.
3. Patients who are known to be homozygous for the UGT1A1*28 or
UGT1A1*6 allele or heterozygous for both.
4. Concurrent administration of herbal preparations and current or anticipated need for food or drugs that are known substrates of UGT1A9 (e.g. propofol, propanolol). PF-05212384 is a strong UGT1A9 inhibitor.
5. Acetaminophen use within 24 hours of the first dose of PF-05212384 (see Section 5.4).
6. Prior therapy with an agent that is known or proposed to be active by inhibition of PI3K, and/or mTOR, and/or AKT, and/or EGFR including cetuximab or panitumumab.
7. Patients who have discontinued prior irinotecan treatment due to toxicity or have experienced a severe hypersensitivity reaction to irinotecan or to one of its excipients.
8. Patients with prior radiation to the pelvis or abdomen in the metastatic or locally advanced setting.
9. Patients with a history of Gilbert's syndrome.
10. Patients with unresolved chronic inflammatory bowel disease and/or current unresolved bowel obstruction
11. Patients with clinically significant active bacterial, fungal, or viral infection.
12. Uncontrolled or significant cardiovascular disease as defined by:
-Myocardial infarction within the prior 6 months.
-Uncontrolled angina within the prior 6 months.
-Congestive heart failure within the prior 6 months.
-Diagnosed or suspected congenital long QT syndrome.
-Any history or second or third degree heart block unless with current pacemaker.
-History or clinically significant ventricular arrhythmias such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes.
-Heart rate <50 beats per minute on pre-entry electrocardiogram.
-Uncontrolled hypertension.
13. Patients with a history of interstitial lung disease.
14. Patients with a history of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal antibody or IgG-fusion protein.
15. Patients with other malignancies except those for which the patient has been disease-free for at least 5 years, or adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin.
16. Patients with known active brain metastases. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment for CNS metastases and have recovered from the acute effects of radiation therapy or surgery, have been off of corticosteroid treatment for at least 4 weeks and neurologically stable prior to joining the study.
17. Patients who have undergone any surgery (not including minor procedures such as lymph node biopsy, needle biopsy, or placement of port a cath) within 4 weeks of first dose of study drug; or not fully recovered from any side effects of previous procedures.
18. Patients who have undergone chemotherapy, radiotherapy (other than palliative radiotherapy to lesions that will not be followed for tumor assessment on this study, ie, non target lesions) within 4 weeks or hormonal, biological or investigational agents within 2 weeks of first dose of study drug (or within 5 times the half life of the agent or 6 weeks for mitomycin C o

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cancer [C04]

Colorectal Cancer
MedDRA version: 16.1 Level: PT Classification code 10069755 Term: K-ras gene mutation System Organ Class: 10018065 - General disorders and administration site conditions
MedDRA version: 16.1 Level: PT Classification code 10071972 Term: N-ras gene mutation System Organ Class: 10018065 - General disorders and administration site conditions
MedDRA version: 16.1 Level: LLT Classification code 10052362 Term: Metastatic colorectal cancer System Organ Class: 100000004864

Intervention(s)

Product Code: PF-05212384
Pharmaceutical Form: Lyophilisate for solution for infusion
INN or Proposed INN: not available
CAS Number: 1197160-78-3
Current Sponsor code: PF-05212384
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Product Name: CETUXIMAB
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: CETUXIMAB
CAS Number: 205923-56-4
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 5-

Product Name: IRINOTECAN
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: IRINOTECAN
CAS Number: 97682-44-5
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-

Primary Outcome(s)

Main Objective: To investigate whether PF-05212384 in combination with irinotecan is superior to cetuximab in combination with irinotecan in prolonging PFS in patients with KRAS and NRAS wild type mCRC who have progressed following prior treatment with irinotecan, oxaliplatin, and fluoropyrimidine.

Secondary Objective: -To confirm the recommended Phase2 Dose (RP2D) of PF-05212384 in combination with irinotecan in Japanese patients (Japanese LIC only)
-To further characterize the anti-tumor activity of PF-05212384 in combination with irinotecan vs cetuximab in combination with irinotecan in patients with KRAS and NRAS wild type mCRC(randomized portion only)
-To characterize and compare the safety of PF-05212384 in combination with irinotecan and cetuximab in combination with irinotecan in patients with KRAS and NRAS wild type mCRC(randomized portion only)
-To characterize the effects of the combination on the potential to prolong the QTc interval(randomized portion and Japanese LIC)
-To assess the PK of PF-05212384 and irinotecan(randomized portion and Japanese LIC)
-To correlate study drug efficacy to gene and proteomics biomarkers related to the EGFR, PI3K/mTOR, and other oncogenic pathways in tumor tissue(randomized portion and Japanese LIC)
Refer to protocol for the rest of sec. objectives

Timepoint(s) of evaluation of this end point: The primary analysis for PFS will take place after 110 PFS events in patients who have centrally confirmed KRAS and NRAS wild type status, with a futility analysis after 55% of the events have occurred.

Primary end point(s): Progression-free suvival (PFS), as assessed by Investigators.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: -LIC (in Japanese patients only) first cycle unaccept.toxicity: Cycle 1
-Tumor assessments: Within 28 days prior to Cycle 1 and then every 8 weeks after Cycle 1 Day 1.
-AEs and lab abnormalities: Cycle 1 (for LIC first cycle unaccep.toxicity) and cycles beyond according to scheme. All cycles for Phase 2.
-PK parameters: See scheme.
-QTc interval: At Screening, Cycle 2 (Arm A only) and as clinically indicated.
-Gene sequences and/or gene copy numbers and signaling proteins in biopsied tumor: At Screening
-Duration of response: At time of final PFS analysis.
-OS: Patients are followed until death or 18 months after last patient is randomized.
-PRO as assessed by HRQoL: Prior to dosing and prior to study procedures on Day 1 of each cycle, end of treatment. and follow-up visits.

Secondary end point(s): -First cycle unacceptable toxicity (lead-in cohort in Japanese patients only)
-Objective response (OR), as assessed using the Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1
-Duration of response (DR)
-Overall survival (OS)
-Safety, including assessment of adverse events and laboratory abnormalities
-QTc interval
-Pharmacokinetic parameters of PF-05212384 and irinotecan/SN-38
-Levels of signaling proteins such as p Akt, Akt, PTEN, p S6, p Met, mTOR, p-EGFR and EGFR in paired tumor biopsies
-Gene sequences and/or gene copy numbers in biopsied tumor tissue relating to EGFR, PI3K and other oncogenic pathways; examples include but are not limited to PIK3CA, PIK3R1, KRAS, NRAS and BRAF sequences and PIK3CA gene amplification
-PRO as assessed by health-related quality of life (HRQoL) instruments

Secondary ID(s)

104846

B2151005

2013-002095-40-BE

Source(s) of Monetary Support

Pfizer Inc., 235 East 42nd Street, New York, NY 10017