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All Drugs and Chemicals

Crizotinib

Eligible patients will be treated with Lorlatinib at the dose of 100 mg QD p.o.

Lorlatinib is a novel small-molecule ROS1/ALK inhibitor that was optimized for robust brain penetration.

Lorlatinib

This is a phase II study assessing response rate to PF-06463922 in patients with ROS1 translocation resistant to previous crizotinib therapy. Eligible patients will be treated with the study drug until disease progression, unacceptable toxicity or patient refusal. Disease assessment will be performed every 8 weeks according to RECIST criteria.

PF-06463922 is a novel small-molecule ROS1/ALK inhibitor that was optimized for robust brain penetration. The results showed that PF-06463922 is most potent against ROS1 and ALK, with selectivity ratios \>100-fold for ROS1 over the 204 kinases tested. A recent study has investigated the activity of PF-06463922 against the crizotinib-resistant ROS1G2032R mutation in both recombinant enzyme and cell-based assays. PF-06463922 effectively inhibited the catalytic activity of recombinant ROS1G2032R and the CD74-ROS1G2032R fusion kinase in BaF3 cells. This effect translated directly into an antiproliferative response. These results, together with its exquisite ROS1 potency and ability to suppress the resistant ROS1 mutations, supports the clinical evaluation of PF-06463922 in ROS1-positive NSCLC, including patients who have developed resistance to crizotinib because of the acquired G2032R mutation and/or brain metastases.

This is a phase II study assessing response rate to PF-06463922 in patients with ROS1 translocation resistant to previous crizotinib therapy. Eligible patients will be treated with the study drug until disease progression, unacceptable toxicity or patient refusal. Disease assessment will be performed every 8 weeks according to RECIST criteria.

PF-06463922 for Crizotinib Pretreated ROS1 Positive Non-small-cell Lung Cancer

PF-06463922 for Crizotinib Pretreated ROS1 Positive Non-small-cell Lung Cancer: a Phase II Trial (PFROST)

Response rate to PF-06463922 in patients with ROS1 translocation resistant to crizotinib

Progression-free survival (PFS) will be calculated from the time between the baseline/start of treatment visit to the time of first occurrence of progressive disease (PD) or death from any cause. Patients who have neither progressed nor died at time of analysis will be censored at the date of last tumor assessment where non progression was documented (i.e. CR, PR or SD)

Overall survival (OS) will be calculated from the time between the baseline/start of treatment visit to the date of death, irrespective of the cause of death. Patients still alive at the time of analysis will be censored at the date they were last known to be alive

Patients will be closely monitored for signs and symptoms of potential adverse events, and will undergo frequent laboratory tests to assess lipids, pancreas, liver, kidney, and haematological function.

Correlation with additional tumor biomarkers in tumor tissue or blood

Clinical research technology Srl

Fondazione Ricerca Traslazionale

Amino Acids

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Single-arm trial whereby all consented, enrolled, eligible patients receive crizotinib

Pfizer CT.gov Call Center

To assess treatment effectiveness and safety of oral crizotinib administered to East Asian patients with Advanced Non-Small Cell Lung Cancer (NSCLC) that is confirmed to be positive for a ROS1 positive gene mutation (translocation or inversion) and confirmed negative for an ALK mutation

Phase II Safety and Efficacy Study of Crizotinib in East Asian Patients With ROS1 Positive, ALK Negative Advanced NSCLC

Phase II, Open Label, Single Arm Study of the Efficacy and Safety of Crizotinib in East Asian Patients With Advanced ALK-Negative NSCLC Harboring a Translocation or Inversion Involving the c-ROS Oncogene (ROS1) Locus

Overall objective response (ORR) was defined as the number of patients with a best overall response of confirmed Complete Response or confirmed Partial Response according to RECIST v1.1 (as determined by Independent Radiology Review \[IRR\]), relative to the total population of response-evaluable participants. Per RECIST v1.1, CR: disappearance of all target lesions. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis); PR: at least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. Confirmed responses were those that persisted on repeat imaging at least 4 weeks after the initial documentation of response.

DR: time from first documentation of objective tumor response (CR or PR) to first documentation of objective progressive disease (PD) or to death due to any cause, whichever occurred first. If no progression or death on study was observed, or given antitumor treatment other than study drug, participants were censored on date of last on-study tumor assessment. RECIST v1.1, a) PD: \>=20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is the smallest on study), sum must also demonstrate an absolute increase of \>=5 mm, appearance of 1 or more new lesions, unequivocal progression of existing non-target lesions; b) CR: disappearance of all target lesions. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis); c) PR: \>=30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters.

TTR was defined as the time from the date of first dose to first documentation of objective tumor response (CR or PR), that was subsequently confirmed. For participants proceeding from PR to CR, the onset of PR was taken as the onset of response. RECIST v1.1 (as determined by IRR), a) CR: disappearance of all target lesions. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis); b) PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

DCR at 8 weeks was defined as the percentage of participants with a confirmed CR, confirmed PR, or stable disease (SD) at 8 weeks, respectively, relative to the total population of response evaluable participants. RECIST v1.1 (as determined by IRR), a) CR: disappearance of all target lesions. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis); b) PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

PFS was defined as the time from the date of the first dose of crizotinib to first documentation of objective PD or to death on study due to any cause, whichever occurred first. If no progression or death on study was observed, or given antitumor treatment other than study drug, participants were censored on date of last on-study tumor assessment. RECIST v1.1, PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered a sign of progression. Unequivocal progression of existing non-target lesions.

OS was defined as the time from the date of the first dose of crizotinib to the date of death due to any cause. For participants still alive at the time of analysis, the OS time was censored on the last date the participants were known to be alive.

Treatment-emergent AEs :between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Relatedness to crizotinib was assessed by the investigator. Treatment-related AE: any untoward medical occurrence attributed to study drug in a participant who received study drug. Serious adverse event (SAE):an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Grade 3 (Severe) events=unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment. Grade 4 (Life-threatening) events caused participant to be in imminent danger of death.

Laboratory values included hemoglobin increased, anemia, platelet count decreased, leukocytosis, white blood cell decreased, lymphocyte count increased, lymphocyte count decreased and neutrophil count decreased. Laboratory values were defined as National Cancer Institute Common Toxicity Criteria for Adverse Events Version 3.0 (NCI CTCAE v3.0) grade 3 or higher.

Laboratory values included blood bilirubin increased, alanine aminotransferase increased, aspartate aminotransferase increased, alkaline phosphatase increased, hypoalbuminemia, hypernatremia, hyponatremia, hyperkalemia, hypokalemia, hypercalcemia, hypocalcemia, hypophosphatemia, Creatinine increased, hyperuricemia, hypermagnesemia, hypomagnesemia, hyperglycemia and hypoglycemia. Laboratory values were defined as National Cancer Institute Common Toxicity Criteria for Adverse Events Version 3.0 (NCI CTCAE v3.0) grade 3 or higher.

The EORTC QLQ-C30 consists of 30 questions which are incorporated into 5 functional domains (physical, role, cognitive, emotional, and social); a global health status/global QOL scale; 3 symptom scales (fatigue, pain, nausea and vomiting scales); and 6 single items that assess the additional symptoms (dyspnea, appetite loss, sleep disturbance/insomnia, constipation, and diarrhea) and the perceived financial burden of treatment. All the scales and single-item scores ranged from 0 to 100, higher score is indicative of a higher response level (high score for a functional scale represents a high / healthy level of functioning; high score for the global health status / QoL represents a high QoL; a high score for a symptom scale / item represents a high level of symptomatology / problems).

The EORTC QLQ-LC13 consisted of 1 multi-item scale and 9 single items that assessed specific symptoms (dyspnea, cough, hemoptysis, and site-specific pain), side effects (sore mouth, dysphagia, neuropathy, and alopecia). Scores on each scale and item ranged from 0 to 100, higher score is indicative of a higher response level (a high score for a symptom scale / item represents a high level of symptomatology / problems).

OxOnc Development LP

Pfizer

Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.

Participants received crizotinib 250 mg orally twice a day in a cycle of 28 days. Dose was modified by investigator if there was treatment-related toxicity. Maximum treatment exposure time was of 291.9 weeks up to final analysis date.

Crizotinib 250 mg

Age, Continuous

Sex: Female, Male

Asian

Race/Ethnicity, Customized

Asia

Region of Enrollment

The Safety Population contains all enrolled participants who received at least one dose of study medication.

Due to small percentage of participants (less than 20%) after Cycle 60, data for EORTC QLQ-C30 score and EORTC QLQ-LC13 score could not be interpreted.

65 participants died during the whole study: 15 participants died within 28 days from last dose of study treatment and were reported as SAEs, while 50 participants died during the survival follow-up.

Pfizer ClinicalTrials.gov Call Center

The response-evaluable population (RES) population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline tumor assessment.

Independent Radiology Reviewed Overall Objective Response (ORR)

The RES population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline tumor assessment. Here, "Overall Number of Participants Analyzed" signifies number of participants with a confirmed objective response that could have occurred anytime up to 151.3 weeks.

IRR-Assessed Duration of Response (DR)

IRR-Assessed Time to Tumor Response (TTR)

The RES population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline tumor assessment.

IRR Assessed Disease Control Rate (DCR) at 8 Weeks

The safety analysis population (SAF) included all enrolled participants who received at least 1 dose of study medication.

IRR-Assessed Progression Free Survival (PFS)

SAF included all enrolled participants who received at least 1 dose of study medication.

Overall Survival (OS)

Incidence of All-Causality Adverse Events

Incidence of All-Causality Serious Adverse Events

Incidence of Treatment Related Adverse Events

Incidence of Treatment Related Serious Adverse Events

Incidence of All-Causality Grade 3-4 Adverse Event

Incidence of Treatment Related Grade 3-4 Adverse Event

Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious AEs, Treatment Emergent Treatment Related AEs and SAEs, Grade 3 or 4 Treatment Emergent AEs and Grade 3 or 4 Treatment Emergent Treatment Related AEs

Hemoglobin Increased: Baseline Grade 0 to Worst Grade 3

Hemoglobin Increased: Baseline Grade 1 to Worst Grade 3

Hemoglobin Increased: Baseline Grade 2 to Worst Grade 3

Hemoglobin Increased: Baseline Grade 0 to Worst Grade 4

Hemoglobin Increased: Baseline Grade 1 to Worst Grade 4

Hemoglobin Increased: Baseline Grade 2 to Worst Grade 4

Anemia: Baseline Grade 0 to Worst Grade 3

Anemia: Baseline Grade 1 to Worst Grade 3

Anemia: Baseline Grade 2 to Worst Grade 3

Anemia: Baseline Grade 0 to Worst Grade 4

Anemia: Baseline Grade 1 to Worst Grade 4

Anemia: Baseline Grade 2 to Worst Grade 4

Platelet Count Decreased: Baseline Grade 0 to Worst Grade 3

Platelet Count Decreased: Baseline Grade 1 to Worst Grade 3

Platelet Count Decreased: Baseline Grade 2 to Worst Grade 3

Platelet Count Decreased: Baseline Grade 0 to Worst Grade 4

Platelet Count Decreased: Baseline Grade 1 to Worst Grade 4

Platelet Count Decreased: Baseline Grade 2 to Worst Grade 4

Leukocytosis: Baseline Grade 0 to Worst Grade 3

Leukocytosis: Baseline Grade 1 to Worst Grade 3

Leukocytosis: Baseline Grade 2 to Worst Grade 3

Leukocytosis: Baseline Grade 0 to Worst Grade 4

Leukocytosis: Baseline Grade 1 to Worst Grade 4

Leukocytosis: Baseline Grade 2 to Worst Grade 4

White Blood Cell Decreased: Baseline Grade 0 to Worst Grade 3

White Blood Cell Decreased: Baseline Grade 1 to Worst Grade 3

White Blood Cell Decreased: Baseline Grade 2 to Worst Grade 3

White Blood Cell Decreased: Baseline Grade 0 to Worst Grade 4

White Blood Cell Decreased: Baseline Grade 1 to Worst Grade 4

White Blood Cell Decreased: Baseline Grade 2 to Worst Grade 4

Lymphocyte Count Increased: Baseline Grade 0 to Worst Grade 3

Lymphocyte Count Increased: Baseline Grade 1 to Worst Grade 3

Lymphocyte Count Increased: Baseline Grade 2 to Worst Grade 3

Lymphocyte Count Increased: Baseline Grade 0 to Worst Grade 4

Lymphocyte Count Increased: Baseline Grade 1 to Worst Grade 4

Lymphocyte Count Increased: Baseline Grade 2 to Worst Grade 4

Lymphocyte Count Decreased: Baseline Grade 0 to Worst Grade 3

Lymphocyte Count Decreased: Baseline Grade 1 to Worst Grade 3

Lymphocyte Count Decreased: Baseline Grade 2 to Worst Grade 3

Lymphocyte Count Decreased: Baseline Grade 0 to Worst Grade 4

Lymphocyte Count Decreased: Baseline Grade 1 to Worst Grade 4

Lymphocyte Count Decreased: Baseline Grade 2 to Worst Grade 4

Neutrophil Count Decreased: Baseline Grade 0 to Worst Grade 3

Neutrophil Count Decreased: Baseline Grade 1 to Worst Grade 3

Neutrophil Count Decreased: Baseline Grade 2 to Worst Grade 3

Neutrophil Count Decreased: Baseline Grade 0 to Worst Grade 4

Neutrophil Count Decreased: Baseline Grade 1 to Worst Grade 4

Neutrophil Count Decreased: Baseline Grade 2 to Worst Grade 4

SAF included all enrolled participants who received at least 1 dose of study medication. Here, "number analyzed" signifies participants evaluable at specific rows.

Number of Participants With a Shift in Hematology Laboratory Results From Baseline Grade </=2 to Worst Grade 3 or Grade 4

Blood Bilirubin Increased: Baseline Grade 0 to Worst Grade 3

Blood Bilirubin Increased: Baseline Grade 1 to Worst Grade 3

Blood Bilirubin Increased: Baseline Grade 2 to Worst Grade 3

Blood Bilirubin Increased: Baseline Grade 0 to Worst Grade 4

Blood Bilirubin Increased: Baseline Grade 1 to Worst Grade 4

Blood Bilirubin Increased: Baseline Grade 2 to Worst Grade 4

Alanine Aminotransferase Increased: Baseline Grade 0 to Worst Grade 3

Alanine Aminotransferase Increased: Baseline Grade 1 to Worst Grade 3

Alanine Aminotransferase Increased: Baseline Grade 2 to Worst Grade 3

Alanine Aminotransferase Increased: Baseline Grade 0 to Worst Grade 4

Alanine Aminotransferase Increased: Baseline Grade 1 to Worst Grade 4

Alanine Aminotransferase Increased: Baseline Grade 2 to Worst Grade 4

Aspartate Aminotransferase Increased : Baseline Grade 0 to Worst Grade 3

Aspartate Aminotransferase Increased : Baseline Grade 1 to Worst Grade 3

Aspartate Aminotransferase Increased : Baseline Grade 2 to Worst Grade 3

Aspartate Aminotransferase Increased : Baseline Grade 0 to Worst Grade 4

Aspartate Aminotransferase Increased : Baseline Grade 1 to Worst Grade 4

Aspartate Aminotransferase Increased : Baseline Grade 2 to Worst Grade 4

Alkaline Phosphatase Increased : Baseline Grade 0 to Worst Grade 3

Alkaline Phosphatase Increased : Baseline Grade 1 to Worst Grade 3

Alkaline Phosphatase Increased : Baseline Grade 2 to Worst Grade 3

Alkaline Phosphatase Increased : Baseline Grade 0 to Worst Grade 4

Alkaline Phosphatase Increased : Baseline Grade 1 to Worst Grade 4

Alkaline Phosphatase Increased : Baseline Grade 2 to Worst Grade 4

Hypoalbuminemia: Baseline Grade 0 to Worst Grade 3

Hypoalbuminemia: Baseline Grade 1 to Worst Grade 3

Hypoalbuminemia: Baseline Grade 2 to Worst Grade 3

Hypoalbuminemia: Baseline Grade 0 to Worst Grade 4

Hypoalbuminemia: Baseline Grade 1 to Worst Grade 4

Hypoalbuminemia: Baseline Grade 2 to Worst Grade 4

Hypernatremia: Baseline Grade 0 to Worst Grade 3

Hypernatremia: Baseline Grade 1 to Worst Grade 3

Hypernatremia: Baseline Grade 2 to Worst Grade 3

Hypernatremia: Baseline Grade 0 to Worst Grade 4

Hypernatremia: Baseline Grade 1 to Worst Grade 4

Hypernatremia: Baseline Grade 2 to Worst Grade 4

Hyponatremia: Baseline Grade 0 to Worst Grade 3

Hyponatremia: Baseline Grade 1 to Worst Grade 3

Hyponatremia: Baseline Grade 2 to Worst Grade 3

Hyponatremia: Baseline Grade 0 to Worst Grade 4

Hyponatremia: Baseline Grade 1 to Worst Grade 4

Hyponatremia: Baseline Grade 2 to Worst Grade 4

Hyperkalemia: Baseline Grade 0 to Worst Grade 3

Hyperkalemia: Baseline Grade 1 to Worst Grade 3

Hyperkalemia: Baseline Grade 2 to Worst Grade 3

Hyperkalemia: Baseline Grade 0 to Worst Grade 4

Hyperkalemia: Baseline Grade 1 to Worst Grade 4

Hyperkalemia: Baseline Grade 2 to Worst Grade 4

Hypokalemia: Baseline Grade 0 to Worst Grade 3

Hypokalemia: Baseline Grade 1 to Worst Grade 3

Hypokalemia: Baseline Grade 2 to Worst Grade 3

Hypokalemia: Baseline Grade 0 to Worst Grade 4

Hypokalemia: Baseline Grade 1 to Worst Grade 4

Hypokalemia: Baseline Grade 2 to Worst Grade 4

Hypercalcemia: Baseline Grade 0 to Worst Grade 3

Hypercalcemia: Baseline Grade 1 to Worst Grade 3

Hypercalcemia: Baseline Grade 2 to Worst Grade 3

Hypercalcemia: Baseline Grade 0 to Worst Grade 4

Hypercalcemia: Baseline Grade 1 to Worst Grade 4

Hypercalcemia: Baseline Grade 2 to Worst Grade 4

Hypocalcemia: Baseline Grade 0 to Worst Grade 3

Hypocalcemia: Baseline Grade 1 to Worst Grade 3

Hypocalcemia: Baseline Grade 2 to Worst Grade 3

Hypocalcemia: Baseline Grade 0 to Worst Grade 4

Hypocalcemia: Baseline Grade 1 to Worst Grade 4

Hypocalcemia: Baseline Grade 2 to Worst Grade 4

Hypophosphatemia: Baseline Grade 0 to Worst Grade 3

Hypophosphatemia: Baseline Grade 1 to Worst Grade 3

Hypophosphatemia: Baseline Grade 2 to Worst Grade 3

SAF included all enrolled participants who received at least one dose of study medication. Here, "number analyzed" signifies participants evaluable at specific rows.

Number of Participants With a Shift of Chemistry Laboratory Results From Baseline Grade </=2 to Worst Grade 3 or Grade 4

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
PF-06463922 for Crizotinib Pretreated ROS1 Positive Non-small-cell Lung Cancer	NCT03439215	Carcinoma, Non-...	Lorlatinib	18 Years -	Fondazione Ricerca Traslazionale
Phase II Safety and Efficacy Study of Crizotinib in East Asian Patients With ROS1 Positive, ALK Negative Advanced NSCLC	NCT01945021	Non Small Cell ... ROS1 Proto Onco... Crizotinib	Crizotinib	18 Years -	Pfizer

Spots Global Cancer Trial Database for ros1 positive