| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Anaplastic Lymphoma Kinase (ALK)-positive (ALK+) or ROS oncogene 1 (ROS1)-positive (ROS1+) advanced non-small cell lung cancer (NSCLC). |
|
| E.1.1.1 | Medical condition in easily understood language |
| a specific type of advanced lung cancer |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066490 |
| E.1.2 | Term | Progression of non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| 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 |
This study has separate primary objectives for the two study portions: Phase 1 and Phase 2.
Phase 1 study portion:
To assess safety and tolerability of PF-06463922 as a single agent at increasing dose levels in patients with advanced ALK+ or advanced ROS1+ NSCLC in order to estimate the Maximum Tolerated Dose (MTD) and select the Recommended Phase 2 Dose (RP2D).
Phase 2 study portion:
To evaluate overall (intra- and extra-cranial) and intracranial anti-tumor activity of single-agent PF-06463922 at RP2D in patients with advanced ALK+ NSCLC and advanced ROS1+ NSCLC.
|
|
| E.2.2 | Secondary objectives of the trial |
| Please refer to study protocol to check separate secondary objectives for the two study portions Phase 1 and Phase 2. |
|
| 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 |
- During the Phase 1 portion of the study, a midazolam (MDZ) drug-drug interaction (DDI) substudy will be conducted at 3 to 4 PF-06463922 dose levels to evaluate the effect of PF-06463922 on CYP3A inhibition/
induction. Additionally, a food effect substudy will be conducted in approximately 6 patients enrolled in Phase 1.
- During the Phase 2 portion of the study, a MDZ DDI substudy and a food effect substudy will be conducted at the Recommended Phase 2 Dose (RP2D) in advanced ALK+ NSCLC patients.
- Additionally, to satisfy local regulatory requirements, a Japanese patient only lead in cohort (LIC) will be enrolled to examine the safety and PK of PF-06463922 at a previously tested dose in Phase 1. The LIC
will be conducted at Japanese sites concurrently with the Phase 2 portion of the study.
- Addition of optional crizotinib treatment after PF-06463922 in Phase 2 for ALK+ NSCLC patients who were treatment naïve prior to receiving PF-06463922. |
|
| E.3 | Principal inclusion criteria |
1. Evidence of histologically or cytologically confirmed diagnosis of metastatic NSCLC (Stage IV, AJCC v7.0) that carries an ALK rearrangement, as determined by the Food and Drug Administration (FDA)-approved FISH assay (Abbott Molecular Inc) or by Immunohistochemistry (IHC) (Ventana Inc), or a ROS1 rearrangement as determined by FISH or RT-PCR or Next Generation Sequencing (NGS) via a local diagnostic test (LDT). A central laboratory confirmation by a Sponsor-selected, validated test will retrospectively determine final ROS1 status. All patients (ALK positive and ROS1 positive) must have archival tissue sample available and collected prior to enrollment.
2. Disease Status Requirements
Phase 1: ALK-positive NSCLC patients must either be treatment naïve in the advanced setting or have had disease progression after atleast 1 previous ALK inhibitor therapy(ies). ROS1+positive NSCLC patients must either be treatment naïve in the advanced setting or have had disease progression after atleast 1 previous ROS1 inhibitor therapy(ies).
Phase 2: ALK-positive NSCLC patients must either be or have had:
- Treatment naïve (ie, no prior chemotherapy in the metastatic disease
setting and no prior ALK inhibitor therapy allowed) [EXP-1];
- Disease progression after crizotinib only. No prior chemotherapy is
allowed in the metastatic disease setting. [EXP-2];
- Disease progression after crizotinib and 1 or 2 prior regimens of
chemotherapy in the metastatic disease setting. [EXP-3];
- Disease progression after 1 prior ALK inhibitor therapy other than
crizotinib. Patients may have had any number of prior chemotherapy
regimens in any disease setting. [EXP-3];
- Disease progression after 2 prior ALK inhibitor therapies. Patients may
have had any number of prior chemotherapy regimens in any disease
setting. [EXP-4];
- Disease progression after 3 prior ALK inhibitor therapies. Patients may
have had any number of prior chemotherapy regimens in any disease
setting. [EXP-5];
ROS1- positive NSCLC patients may be:
- Treatment naïve (ie, no prior chemotherapy in the metastatic disease setting and no prior ROS inhibitor therapy). [EXP-6];
- Any number of prior therapies (ie, chemotherapy and/or ROS inhibitor therapies). [EXP-6].
-3. Tumor Requirements:
Phase 1: All Patients must have at least one measurable target extracranial lesion according to RECIST v1.1. In addition patients with asymptomatic CNS metastases (including patients asymptomatic by means of stable or decreasing doses of steroids within the last 2 weeks prior to study entry) will be eligible. The brain metastases may be newly diagnosed or be present as progressive disease after surgery, whole brain radiotherapy or stereotactic radiosurgery (see Exclusion Criterion #3 for the lapsed time period required between the end of radiotherapy and study entry). Patients who have asymptomatic radiologically suspected leptomeningeal disease (LM) or carcinomatous meningitis (CM) and negative spinal fluid (CSF) are eligible to enter Phase 1.
Phase 2: All Patients must have at least one measurable target extracranial lesion according to RECIST v1.1. In addition patients with asymptomatic CNS metastases (including patients controlled with stable or decreasing steroid use within the last 2 weeks prior to study entry) will be eligible. The brain metastases may be newly diagnosed or be present as progressive disease after surgery, whole brain radiotherapy or stereotactic radiosurgery (see Exclusion Criterion #3 for the lapsed time period required between the end of radiotherapy and study entry). Patients who have leptomeningeal disease (LM) or carcinomatous meningitis (CM) will be eligible if the LM/CM is visualized on MRI or if documented baseline cerebral spinal fluid (CSF) positive cytology is available.
4. Age >=18 years (or ≥20 years of age if required by local regulation).
5. ECOG Performance Status (PS):
- Phase 1: 0 or 1;
- Phase 2: 0, 1, or 2.
6. Adequate Bone Marrow Function, including:
- Absolute Neutrophil Count (ANC) >=1.5 x 1 000 000 000/L;
- Platelets >=100 x 1 000 000 000/L;
- Hemoglobin >=9 g/dL.
7. Adequate Pancreatic Function, including:
- Serum total amylase <=1.5 ULN.
- Serum lipase <=1.5 ULN.
8. Adequate Renal Function, including:
- Serum creatinine <=1.5 x ULN or estimated creatinine clearance >=60 mL/min as calculated using the method standard for the institution.
9. Adequate Liver Function, including:
- Total serum bilirubin <=1.5 x ULN;
- Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT)
<=2.5 x ULN; <=5.0 x ULN if there is liver metastases involvement;
10. Acute effects of any prior therapy resolved to baseline severity or to CTCAE Grade <=1 except for AEs that in the investigator' judgment do not constitute a safety risk for the patient.
For more inclusion criteria refer to the protocol. |
|
| E.4 | Principal exclusion criteria |
1.Spinal cord compression is excluded unless the patient demonstrates good pain control attained through therapy and there is stabilization or recovery of neurological function for the 4 weeks prior to study entry
2.Major surgery within 4 weeks of study entry.Minor surgical procedures are not excluded but sufficient time should have passed for wound healing
3.Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study entry.Palliative radiation (<=10 fractions) must have been completed at least 48 hours prior to study entry.Stereotactic or small field brain irradiation must have completed at least 2 weeks prior to study entry.Whole brain radiation must have completed at least 4 weeks prior to study entry
4.Systemic anti-cancer therapy completed within a minimum of 5 halflives of study entry (unless clinically meaningful tumor flare per discretion of the investigator, in which discussion with the sponsor is warranted).
5.Prior therapy with an antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways, including, but not limited to, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T
lymphocyte associated antigen 4 (anti-CTLA-4) antibody.
6.Previous high-dose chemotherapy requiring stem cell rescue
7.Prior irradiation to >25% of the bone marrow
8.Active and clinically significant bacterial, fungal, or viral infection including HBV, HCV, known HIV or AIDS-related illness
9.Clinically significant cardiovascular disease (that is, active or <3 months prior to enrollment): cerebral vascular accident/stroke, myocardial infarction,
unstable angina, congestive heart failure (New York Heart Association Classification Class ≥ II), second-degree or thirddegree AV block (unless paced) or
any AV block with PR >220 msec. Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 bpm (unless patient is otherwise healthy such as long-distance runners, etc.), machine-read ECG with QTc >470 msec, or congenital long QT syndrome.
10.Patients with predisposing characteristics for acute pancreatitis according to investigator judgment (see protocol for more details).
11.History of extensive,disseminated,bilateral or presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersentivity pneumonitis, interstitial pneumonia,
interstitial lung disease, obliterative bronchiolitis and pulmonary fibrosis. Patients with history of prior radiation pneumonitis are not excluded
12.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
13.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
14.Evidence of active malignancy within the last 3 years. See protocol for more details
15. Active inflammatory gastrointestinal disease, chronic diarrhea, symptomatic diverticular disease or previous gastric resection or lap band.
For more exclusion criteria refer to the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1 Primary Endpoint:
- Cycle 1 Dose-Limiting Toxicities (DLTs).
Phase 2 Primary Endpoint:
- Objective tumor response, as assessed by Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. In patients with asymptomatic CNS metastases, up to five (5) intracranial target lesions in addition to the five (5) extracranial target lesions will be assessed. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1 Primary Endpoint:
- Cycle 1 Dose-Limiting Toxicities (DLTs): cycle 1.
Phase 2 Primary Endpoint:
- Objective tumor response: at baseline and at the stipulated intervals during treatment.
Please refer to Schedule of Activities of the protocol. |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints [all patients unless otherwise indicated]:
- Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAE v.4.03), seriousness and relationship to study therapy.
- Laboratory abnormalities as characterized by type, frequency and severity (as graded by NCI CTCAE v.4.03).
- Left Ventricular Ejection Fraction (LVEF).
- Vital Signs (heart rate, blood pressure).
- Total Mini-Mental State Examination Score [Phase 1 only].
- Mood assessment, Cognitive Function assessment, Suicidal Ideation and Behavior assessment [Phase 2 only].
- Pharmacokinetic parameters of PF-06463922: Single Dose - Cmax, Tmax, AUClast,AUC t, CL/F, and Vz/F and t1/2, AUCinf as data permit.
Multiple Dose (assuming steady-state is achieved) - Css,max, Tss,max, AUCss,t, t1/2, Css,min, Css,av, CL/F, Vz/F, Rac (AUCss,t/AUCsd,t) and Rss (AUCss,t/AUCsd,inf) as data permit. Phase 1 only: Urine PK parameters (Ae%, and CLR) of PF-06463922 from MDZ and food effect substudy.
- Phase 1 only: Pharmacokinetic parameters of midazolam: Cmax, Tmax, AUClast, CL/F, and Vz/F and t1/2, AUCinf as data permit.
- Patient reported functioning and impact on disease/treatment-related symptoms of lung cancer and global QOL.
- QTc interval.
- Disease Control Rate (DCR) at 12 weeks defined as the percent of patients with a confirmed complete response (CR), partial response (PR) or stable disease (SD) according to RECIST 1.1 at 12 weeks.
- Objective tumor response, as assessed by Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 (Appendix 3) [Phase 1 only - primary endpoint in Phase 2]. In patients with asymptomatic CNS metastases, up to 5 intracranial target lesions in addition to the 5 extracranial target lesions will be assessed.
- Time-to-event endpoints: Progression-Free Survival (PFS), Overall Survival (OS) at 1 year and 18 months, Duration of Response (DR), and Time to Tumor Response (TTR).
- Probability of first event being a CNS progression, non CNS progression, or death.
- Time to Progression (TTP) [Phase 2 only].
- Response to prior systemic therapies.
- Selected molecular profiling of tumor tissue, eg, ALK kinase domain mutations and circulating nucleic acid (CNA), eg, ALK kinase domain mutations.
Secondary Endpoints [ALK+ NSCLC Phase 2 patients receiving singleagent crizotinib
following first-line treatment with PF-06463922]:
- Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAE v.4.03), seriousness and relationship to study therapy.
- Laboratory abnormalities as characterized by type, frequency, and severity (as graded
by NCI CTCAE v.4.03).
- Objective tumor response, as assessed by Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1, and time-to-event endpoints including PFS, DR, TTR and OS.
Phase 1 Exploratory Endpoints:
- Time to Progression (TTP).
Phase 1 and 2 Exploratory Endpoints
- CSF concentration of PF-06463922.
Japanese Patient Only Lead-In Cohort (LIC)
- Cycle 1 Dose Limiting Toxicities (DLTs).
Endpoint for Drug-Drug Interaction (DDI)/Holter Monitoring Study
- Pharmacokinetic parameters (as data permit) for probe substrate after single oral administration with or without PF-06463922: Plasma AUC24, AUClast, AUCinf , Cmax, Tmax, CL/F, Vz/F and t1/2.
- Pharmacokinetic parameters (as data permit) for relevant probe substrate metabolite(s) and PF-06463922 metabolite(s): Plasma and AUC24, AUClast, AUCinf , Cmax, Tmax, t1/2, MRCmax, MRAUCinf, and MRAUClast.
- PR interval with PF-06463922 treatment. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to Schedule of Activities of the protocol. |
|
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| To characterize the effect of food on PF-06463922 |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | 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 | 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
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 |
| Australia |
| Belgium |
| Canada |
| France |
| Germany |
| Hong Kong |
| Italy |
| Japan |
| Korea, Republic of |
| Singapore |
| Spain |
| Switzerland |
| Taiwan |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 1 |
| 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 | 1 |
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