| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| metastatic non-small cell lung cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 17.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
• To assess the anti-tumor efficacy of oral single agent PF-02341066 administered to patients with advanced NSCLC after failure of at least one line of chemotherapy and harbor a translocation or inversion event involving the ALK gene locus as measured by ORR;
• To assess the safety and tolerability of oral PF-02341066. |
|
| E.2.2 | Secondary objectives of the trial |
• Assess secondary measures of clinical efficacy including overall survival, duration of response, time to tumor response, disease control rate at 6 & 12 weeks, & progression-free survival;
• Determine PK in this patient population using population PK methods & explore correlations between PK, response &/or safety findings;
• Explore the relationship of ALK gene fusion to the presence of ALK protein & fusion transcript;
• Correlate changes from baseline in expression of biomarkers in signaling pathways (including JAK/STAT, MEK/ERK, & PI3K/AKT pathways) to pharmacokinetic & outcome measures;
• Assess patient reported outcomes of health-related quality of life, disease/treatment-related symptoms of lung cancer, & general health status;
• Evaluate the effect of PF-02341066 on the QT interval;
• Identify & evaluate potential pharmacogenetic markers for possible association with selected observed toxicities, i.e. potential markers of adverse hepatic & renal drug reactions. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| There is not a separate title, date or version for the sub-study,see section 7.3.3.1 of the Protocol. Just a sub-set of patients from the protocol will be in the sub-study. ECG Objective: characterize the effects of PF-02341066 on the QTc interval. |
|
| E.3 | Principal inclusion criteria |
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the trial:
1. Histologically or cytologically proven diagnosis of NSCLC that is locally advanced or metastatic.
2. Positive for translocation or inversion events involving the ALK gene locus (eg, resulting in EML4-ALK fusion) as determined by an ALK break apart FISH assay and defined by an increase in the distance of 5’ and 3’ ALK probes or the loss of the 5’ probe. Once Amendment #10 is approved at an individual site’s IRB/IEC, positive ALK results from other methods such as Immunohistochemistry (IHC) or Reverse Transcriptase Polymerase Chain Reaction (RT-PC) testing may also be acceptable after discussion and approval by the Sponsor.
3. Meets one of the following criteria:
Randomized to Arm B (pemetrexed or docetaxel) of Study A8081007 and was discontinued from treatment due to RECIST version 1.1-defined progression of disease as determined by independent radiology review. Once the primary endpoint of Study A8081007 has been analyzed and the results made available, patients randomized to Arm B of Study A8081007 will be offered treatment with PF-02341066 and allowed to enroll in Study A8081005 without RECIST version 1.1-defined progression of disease as determined by independent radiology review.
However, upon IRB/IEC approval of Amendment 14, patients will not be allowed to cross over from the chemotherapy arm of Study A8081007 without RECIST version 1.1 – defined progression of disease by independent radiology review.
Ineligibility for A8081007 due to (1) prior treatment for advanced disease with more than one chemotherapy regimen, (2) prior treatment with only one chemotherapy regimen for advanced disease and that regimen was not platinum-based, (3) prior treatment with pemetrexed as part of their platinum-based chemotherapy and did not meet the docetaxel eligibility requirements from Protocol A8081007, (4) treated with docetaxel as part of their platinum-based prior chemotherapy but have NSCLC that is predominantly squamous cell carcinoma and thus, not eligible to be dosed with pemetrexed, or (5) ECOG performance status 3 or the laboratory or RECIST eligibility criteria (but must meet all eligibility criteria of this protocol).
Once A8081007 enrollment is closed, patients with only one previous treatment including single agent EGFR tyrosine kinase inhibitor, such as erlotinib or gefitinib, for locally advanced or metastatic NSCLC can be enrolled.
4. Patients with brain metastases are eligible if asymptomatic or if treated must be neurologically stable for at least 2 weeks and are not taking any medications contraindicated in Exclusion Criteria #11-13.
5. Any prior treatment (chemotherapy, radiation [except for palliative] or surgery)must have been completed at least 2 weeks prior to initiation of study medication.
Palliative radiation (≤ 10 fractions) must have been completed 48 hours prior to the start of study treatment. Any acute toxicity must have been recovered to ≤ Grade 1 (except alopecia).
6. Tumors must have measurable disease as per RECIST (version 1.1); see Appendix 6. Once Amendment #10 is approved by an individual’s IRB/IEC, this criterion will no longer be required.
7. Female or male, 18 years of age or older (for patients enrolled in Japan: consent from a legally acceptable representative is required for all patients who are under 20 years old).
8. ECOG performance status 0-3.
9. Adequate organ function as defined by the following criteria.
• Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤2.5 x upper limit of normal (ULN), or AST and ALT ≥5 x ULN if liver function abnormalities are due to underlying malignancy; AST and/or ALT ≥ 5 x ULN if due to underlying malignancy may be enrolled with agreement by the Sponsor;
• Total serum bilirubin ≤1.5 x ULN;
• Absolute neutrophil count (ANC) ≥1500/µL;
• Platelets ≥ 30,000/µL;
• Hemoglobin ≥ 8.0 g/dL;
• Serum creatinine ≤2 x ULN.
10. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all the pertinent aspects of the trial prior to enrollment.
11. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures including completion of the PRO measures.
12. As of amendment 14, male and female patients of childbearing potential must agree to use a highly effective method of contraception throughout the study and for 90 days after the last dose of assigned treatment. 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. Eligibility for Protocol A8081007 until enrollment is closed.
2. No prior systemic treatment, chemotherapy or EGFR tyrosine kinase inhibitor for advanced NSCLC.
3. Current treatment on another therapeutic clinical trial.
4. Prior therapy specifically directed against ALK.
5. Spinal cord compression unless treated with the patient attaining good pain control and stable or recovered neurologic function, carcinomatous meningitis, or leptomeningeal disease.
6. Any of the following within the 3 months prior to starting study treatment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, or cerebrovascular accident including transient ischemic attack.
7. Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, or QTc interval >470 msec.
8. Previous treatment with PF-02341066.
9. [Deleted per Amendment #7].
10. Pregnancy or breastfeeding.
11. Use of drugs or foods that are known potent CYP3A4 inhibitors, including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, and grapefruit or grapefruit juice.
12. Use of drugs that are known potent CYP3A4 inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin,, rifampin, and St. John’s wort.
13. Use of drugs that are CYP3A4 substrates with narrow therapeutic indices, including but not limited to dihydroergotamine, ergotamine, pimozide, astemizole*, cisapride*, and terfenadine* (* withdrawn from U.S. market).
14. Prior malignancy (other than current NSCLC): patients will not be eligible if they have evidence of active malignancy (other than non-melanoma skin cancer or localized cervical cancer, or localized and presumed cured prostate cancer) within the last 3 years.
15. For Japan only: patients who have following complications or symptoms:
• Serious wound such as chronic wound, or Grade ≥3 gastrointestinal ulcer.
• Serious gastrointestinal symptoms such as Grade ≥3 diarrhea.
16. Other severe acute or chronic medical or psychiatric conditions, or laboratory abnormalities that would impart, in the judgment of the investigator and/or sponsor, excess risk associated with study participation or study drug administration, and which would, therefore, make the patient inappropriate for entry into this study.
17. Patients with known interstitial fibrosis or interstitial lung disease. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint:
• ORR;
• Type, incidence, severity, seriousness and relationship to study medications of adverse events (AE) and any laboratory abnormalities. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
ORR: screening/baseline, then every 6 weeks starting from date of first dose, and when clinically indicated if disease progression is suspected, and at disease progression
Safety: from date of first dose to 28 days after last dose |
|
| E.5.2 | Secondary end point(s) |
• OS, DR, TTR, DCR at 6 and 12 weeks, and PFS;
• Plasma concentrations of PF-02341066;
• Types of EML4-ALK fusion variants and ALK protein expression;
• Protein expression of identified biomarkers in serial tumor samples from surgery
or biopsy, when available;
• HRQoL, lung cancer disease treatment-related specific symptoms, and general health status;
• QTc;
• genotypes of alleles possibly associated with adverse hepatic or renal drug reactions, e.g. HLA-DQAI*02:01, PKD1, PKD2, and von Hippel-Lindau (VHL). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Progression Free Survival: date of first dose to date of objective disease progression or date of death, whichever occurs first
Overall Survival: date of first dose to date of death
Duration of Response: from date of first documentation of objective tumor response that is subsequently confirmed to date of first documentation of objective disease progression or death, whichever occurs first
Time To Response: from date of first dose to date first documentation of objective tumor response that is subsequently confirmed |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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 |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 72 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Bulgaria |
| Canada |
| China |
| France |
| Germany |
| Greece |
| Hong Kong |
| Hungary |
| Ireland |
| Italy |
| Korea, Republic of |
| Netherlands |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| United Kingdom |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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