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

Phase 1

• Conditions: Colorectal Cancer; MedDRA version: 16.1Level: PTClassification code 10069755Term: K-ras gene mutationSystem Organ Class: 10018065 - General disorders and administration site conditions; MedDRA version: 16.1Level: PTClassification code 10071972Term: N-ras gene mutationSystem Organ Class: 10018065 - General disorders and administration site conditions; MedDRA version: 16.1Level: LLTClassification code 10052362Term: Metastatic colorectal cancerSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2013-002095-40-ES
• Lead Sponsor: Pfizer Inc.,235 East 42nd Street, New York, NY 10017

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2014-03-11
• Last Update Posted: 9 May 2016

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 150

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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified