| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Colorectal Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Colorectal Cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1b
-To assess safety and to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of the combination of PF-05212384 plus FOLFIRI in patients treated at non-Japanese clinical sites.
Phase 2
-To demonstrate that the combination of PF-05212384 plus FOLFIRI is superior to the combination of bevacizumab plus FOLFIRI in prolonging progression-free survival (PFS) in patients with mCRC who have progressed on a prior oxaliplatin-containing regimen.
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| E.2.2 | Secondary objectives of the trial |
-Lead in cohort (LIC) only: To demonstrate that the RP2D for the combination of PF-05212384 plus FOLFIRI determined in non-Japanese patients is also safe and tolerable in Japanese patients.
-Phase 1b, LIC: To further characterize the anti-tumor activity of PF-05212384 plus FOLFIRI.
-Phase 1b, LIC and Phase 2: To further evaluate the safety of the combination of PF-05212384 and FOLFIRI.
-Phase 1b, LIC and Phase 2 (Arm A only): To assess the pharmacokinetics of FOLFIRI (fluorouracil and irinotecan) and PF-05212384.
-Phase 1b, LIC and Phase 2 (Arm A only): To characterize the potential for prolonged QTc interval.
-Phase 1b, LIC and Phase 2: To correlate study drug efficacy and/or resistance to gene and proteomics biomarkers related to the VEGFR, PI3K/mTOR, and other oncogenic pathways in tumor tissue.
-for a complete list of secondary objectives refer to the protocol. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. 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.
2. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Histologically proven diagnosis of CRC and evidence of metastatic disease not amenable to potentially curative treatment. Archival tumor biopsy specimens, either as a formalinfixed paraffin-embedded (FFPE) tumor tissue block or approximately 15-20 (minimum of 10) unstained slides, are required for biomarker analyses.
4. The first 25 patients of both Arms of the Phase 2, must be willing to provide fresh paired tumor biopsies at baseline and on-study for the pharmacodynamic biomarker studies (additional information can be found in the protocol).
5. Phase 2 only: KRAS status (using an archived or a fresh biopsy) must be known prior to randomization, using locally available test results or by a central review.
6. Progression on prior oxaliplatin-containing regimen used in 1st line setting for mCRC or progression within 6 months of end of oxaliplatin-containing regimen in the adjuvant setting.
7. Measurable disease per RECIST v. 1.1 (Phase 2 only).
8. Adequate bone marrow function:
-Absolute neutrophil count (ANC) ≥1500/mm 3 or ≥1.5 x 10 9/L;
-Platelets ≥100 x 10 9/L;
-Hemoglobin ≥9 g/dL.
9. Adequate renal function:
-Serum Creatinine (Cr) ≤1.5 x upper limit of normal (ULN) or estimated CrCl ≥60 ml/min per institutional standard method of calculation.
10. Adequate hepatic function:
-Total serum bilirubin ≤1.5 x ULN;
-Aspartate and Alanine Aminotransferase ≤2.5 x ULN; ≤5.0 x ULN in presence of hepatic metastases;
-Alkaline phosphatase ≤2.5 x ULN; ≤5.0 x ULN in presence of bone metastases.
11. Adequate glucose control, as defined by HbA1c <7% and fasting blood glucose ≤126 mg/dL.
12. Age ≥18 years (≥20 years if required by local regulation).
13. ECOG performance status 0, 1 or 2 (not declining within 2 weeks prior to signing of informed consent).
14. Resolution of all acute toxic effects of prior therapy or surgical procedures to ≤Grade 1 except alopecia.
15. Serum/urine pregnancy test (for females of childbearing potential) negative at screening and at the baseline visit (before the patient may receive the investigational product).
16. Male or female patients of childbearing potential must agree to use two (2) highly effective method of contraception throughout the study and for at least 90 days after the last dose of assigned treatment (180 days if required by local regulation). The principal Investigator or designee will determine what is considered effective contraception. A patient is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.
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| E.4 | Principal 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. Participation in other studies involving investigational drug(s) (Phases 1-4) during study participation.
3. Other severe acute or chronic medical or psychiatric condition (including recent (within the past year) or active suicidal ideation or behavior) or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
4.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 (or within 5 times the half life of the agent) of first dose of study drug.
5. Prior irinotecan treatment.
6. Patients with RAS (KRAS/NRAS) wild type mCRC not previously treated with an anti-EGFR containing regimen unless such treatment is contraindicated.
7. Patients with unresolved inflammatory bowel disease and/or current unresolved bowel obstruction.
8. Patients with contraindications in case of known hypersensitivity to calcium folinate, or to any of the excipients and/or pernicious anaemia or other anaemias due to vitamin B12 deficiency.
9. Patients with contraindications in case of hypersensitivity to the active substance or to any of the excipients and/or to hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanised antibodies.
10. History of dihydropyrimidine dehydrogenase deficiency disorder.
11. Patients with prior radiation to the pelvis or abdomen in the metastatic or locally advanced setting.
12. History of Gilbert’s syndrome.
13. Other malignancies EXCEPT those for which the patient has been disease-free for at least 5 years or adequately treated basal cell or squamous cell skin cancer, carcinoma in-situ of the cervix.
14. History of coagulopathy or bleeding diathesis or active bleeding of any cause or NCI CTCAE Grade 3 or greater hemorrhage from any cause within 4 weeks prior to screening (Phase 2).
15. Hypertension that cannot be controlled by medications (>150/100 mmHg despite optimal medical therapy).
16. Patients with known active brain metastases. Patients with previously diagnosed brain metastases are eligible if they have completed their CNS treatment and have recoveredfrom the acute effects of radiation therapy or surgery prior to the start of the study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable.
17. Major surgery within 4 weeks of baseline disease assessments; or not fully recovered from any side effects of previous procedures.
18. Minor procedures such as lymph node biopsy, needle biopsy, or placement of port-acaths within 2 weeks of baseline disease assessments; or not fully recovered from any side effects of previous procedures.
19. Uncontrolled or significant cardiovascular disease, as defined by any of the following:
-Myocardial infarction within prior 6 months;
-Uncontrolled angina in prior 6 months;
-Congestive heart failure in prior 6 months;
-Diagnosed or suspected congenital long QT syndrome;
-Any history or 2nd or 3rd degree heart block unless with current pacemaker;
-History of clinically significant ventricular arrhythmias such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes;
-Heart rate <50 beats/minute on pre-entry electrocardiogram.
For a complete list of exclusion criteria, refer to the protocol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b:
-First cycle Dose Limiting Toxicity (DLT) in patients treated at non-Japanese clinical sites.
Phase 2:
-Progression free survival (PFS), as assessed by investigators.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1b:
-First Cycle Dose Limiting Toxicity will be assessed during the lead-in period and Cycle 1
Phase 2:
-The primary analysis for PFS will take place after 110 PFS events in patients events have occurred with a futility analysis after 55% of the events have occurred.
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| E.5.2 | Secondary end point(s) |
LIC only: First cycle toxicity (DLT).
-Phase 1b, LIC: Objective response (OR, as assessed using the Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1).
-Phase 1b, LIC and Phase 2: Safety including adverse events as characterized by type, frequency, severity (as graded by NCI CTCAE v. 4.0), timing, seriousness and relationship to study therapy and laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v. 4.0) and timing.
-Phase 1b,LIC and Phase 2 (Arm A only): Pharmacokinetic parameters of PF-05212384, irinotecan, and fluorouracil.
-Phase 1b,LIC and Phase 2 (Arm A only): QTc interval.
-Phase 1b,LIC and Phase 2: Gene sequences and/or gene copy numbers in biopsied tumor tissue relating to VEGFR, PI3K and other oncogenic pathways; examples include, but are not limited to, PIK3CA, PIK3R1, KRAS and BRAF sequences and PIK3CA gene amplification.
-Phase 2 only: OR, as assessed using RECIST (version 1.1), Duration of response (DR) and Overall survival (OS).
-Phase 2 only: Levels of signaling proteins such as p-Akt, Akt, PTEN, p- S6, p-Met, p-mTOR, and p-VEGFR in biopsied tumor tissue.
-Phase 2 only: PRO instruments (self-administered FACT-C)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-First cycle toxicity Lead-in cohort -LIC- [Japan only]): lead-in period and Cycle 1
-Tumor assessments: For Phase 1b and LIC tumor assessments will end at EoT visit, for Phase 2 tumor assesments will continue every 8 weeks.
-Duration of response at time of PFS analysis.
-OS: Pats. will be followed until death or 18 m. after Last Patient is randomized.
-AEs + lab abnormalities: At lead-in period for Phase1b and lead-in cohort (Japan sites only) and Cycle 1 and cycles beyond according to scheme for Phase 1b, lead-in cohort and Phase 2.
-PK parameters.: See scheme.
-QTc interval: screening, Cycle 1, Cycle 2, End of Treatment, (see scheme)
-Gene sequences and/or gene copy numbers and signaling proteins in biopsed tumor issue: At screening.
-PRO: Prior to dosing in each cycle.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Patient Reported Outcomes |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase 1B/2-Ph 1b portion (which includes a LIC in Japanese patients) and a Ph 2 randomized portion |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| 2 independent arms- PF-05212384 plus FOLFIRI (Arm A) or bevacizumab plus FOLFIRI (Arm B) |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Canada |
| France |
| Italy |
| Japan |
| Germany |
| Korea, Republic of |
| Spain |
| Poland |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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