Study of Ponatinib in Patients With Lung Cancer Preselected Using Different Candidate Predictive Biomarkers

• ClinicalTrials.gov Identifier: NCT01935336
• Recruitment Status: Completed
• First Posted: September 5, 2013
• Results First Posted: February 11, 2022
• Last Update Posted: February 11, 2022
• Sponsor: University of Colorado, Denver
• Collaborator: Ariad Pharmaceuticals
• Information provided by (Responsible Party): University of Colorado, Denver

Tracking Information

• First Submitted Date: August 27, 2013
• First Posted Date: September 5, 2013
• Results First Submitted Date: April 5, 2021
• Results First Posted Date: February 11, 2022
• Last Update Posted Date: February 11, 2022
• Actual Study Start Date: September 24, 2013
• Actual Primary Completion Date: January 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 19, 2022)

• Biomarker FGFR1 (ISH/SISH) Score (Part A) [ Time Frame: Baseline ]
  Biomarker prevalence and its 95% (exact) confidence interval (CI) among the screening patients and for different histologies will be reported. Molecular cohorts for ISH and SISH positivity: FGFR1 ISH+/SISH+, FGFR1 ISH+/SISH-, FGFR1 ISH-/SISH+, and FGFR1 ISH-/SISH-
• Overlapping Frequency of FGFR1 (ISH/SISH) Biomarkers (Part A) [ Time Frame: Baseline ]
  Overlapping frequency and its 95% CI between biomarkers among the screening patients and for different histologies will also be reported.
• Objective Response Rate (ORR) Per RECIST v1.1 (Part B) [ Time Frame: From date of first dose until date of Disease Progression or death (up to 153 days), whichever occurred first ]
  Evaluated using Fisher's exact test with a descriptive p-value. Summarized using binomial proportions with 95% exact binomial confidence intervals.

Original Primary Outcome Measures (submitted: August 30, 2013)

• Prevalence of each biomarker (Part A) [ Time Frame: Up to 5 years ]
  Biomarker prevalence and its 95% (exact) confidence interval (CI) among the screening patients and for different histologies will be reported.
• Overlapping frequency of biomarkers (Part A) [ Time Frame: Up to 5 years ]
  Overlapping frequency and its 95% CI between biomarkers among the screening patients and for different histologies will also be reported.
• Objective response rate (ORR) per RECIST v1.1 (Part B) [ Time Frame: Up to 5 years ]
  Evaluated using Fisher's exact test with a descriptive p-value. Summarized using binomial proportions with 95% exact binomial confidence intervals.

Current Secondary Outcome Measures (submitted: January 19, 2022)

Incidence of Adverse Events, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 [ Time Frame: From date of first dose until date of Disease Progression (up to 153 days). Assessed at Day 1, Day 8, Day 15 of each 28 day cycle) ]

Adverse events will be tabulated per participant, per organ, and per visit.

Original Secondary Outcome Measures (submitted: August 30, 2013)

Incidence of adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 [ Time Frame: Up to 5 years ]

The number of adverse events and percentages will be tabulated per organ and per visit.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Ponatinib in Patients With Lung Cancer Preselected Using Different Candidate Predictive Biomarkers
• Official Title: A Phase II Study of Ponatinib in Cohorts of Patients With Lung Cancer Preselected Using Different Candidate Predictive Biomarkers
• Brief Summary: This phase II trial studies how well ponatinib hydrochloride works in treating patients with stage III-IV lung cancer. Ponatinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
• Detailed Description: This study will look at the safety and effectiveness of the investigational drug ponatinib in lung cancer. The investigators hope that ponatinib will work against tumors that have certain biomarkers. Therefore, the study will pre-screen patients for these certain biomarkers before enrolling them into the main treatment study. Different doses of ponatinib may be tested in this study.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Adenocarcinoma of the Lung
• Extensive Stage Small Cell Lung Cancer
• Limited Stage Small Cell Lung Cancer
• Recurrent Non-small Cell Lung Cancer
• Recurrent Small Cell Lung Cancer
• Stage IIIA Non-small Cell Lung Cancer
• Stage IIIB Non-small Cell Lung Cancer
• Stage IV Non-small Cell Lung Cancer

Intervention

Drug: Ponatinib

Ponatinib 45mg taken by mouth each day at the same time with or without food

Other Names:

• Iclusig
• AP24534
• Multitargeted tyrosine kinase inhibitor AP24534

Study Arms

Experimental: Ponatinib

Patients receive ponatinib hydrochloride taken by mouth once or twice a day. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Intervention: Drug: Ponatinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 19, 2022): 171
• Original Estimated Enrollment (submitted: August 30, 2013): 110
• Actual Study Completion Date: November 2017
• Actual Primary Completion Date: January 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• PART A: Patients must have histologically or cytologically confirmed locally advanced (after failure of local therapy) or metastatic lung cancer (any histology, except carcinoid) stage IIIa, IIIb or IV
• PART A: Existing formalin fixed paraffin embedded biopsy of the lung cancer with potentially sufficient material for analysis
• PART A: Non-small cell lung cancer (NSCLC) with adenocarcinoma histology must have been previously tested for both epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements
• PART A: Able (physically and financially) to travel to University of Colorado for clinical trial treatment
• PART B: Patients must have histologically or cytologically confirmed locally advanced (after failure of local therapy) or metastatic lung cancer (any histology, except carcinoid) stage IIIa, IIIb or IV
• PART B: Patients must be proven to meet marker criteria (FGFR1 silver in situ hybridization (SISH) + in situ hybridization (ISH) +, FGFR1 SISH+ ISH negative [-ve], FGFR1 SISH-ve ISH+, FGFR1 SISH-ve ISH-ve [FGFR1 double negative cohort] or ret proto-oncogene [RET] FISH+) prior to enrollment into Part B (treatment); adenocarcinoma patients must be known to not possess either an EGFR mutation or an ALK rearrangement in their tumor (if positive for one, testing for both is not required)
• PART B: Patients must have measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
• PART B: Patients may have received any number of lines of prior therapy
• PART B: Life expectancy of >= 3 months
• PART B: Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• PART B: Leukocytes >= 3,000/mcL
• PART B: Absolute neutrophil count >= 1,500/mcL
• PART B: Hemoglobin >= 9 g/dL
• PART B: Platelets >= 100,000/mcL
• PART B: Total bilirubin =< 1.5 x institutional upper limit of normal (ULN), unless due to Gilbert's syndrome
• PART B: Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN
• PART B: Creatinine =< 1.5 X ULN OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• PART B: Serum lipase =< 1.5 X ULN
• PART B: Serum amylase =< 1.5 X ULN
• PART B: Previous treatment related side-effects/adverse events must have resolved to at least grade 1 or, at the discretion of the investigator, select stable grade 2 toxicities (e.g. alopecia or fatigue) may be permissible if unchanging in grade for at least 3 months following discussion with the principal investigator (PI)
• PART B: Patients with central nervous system (CNS) metastases are eligible for enrollment if they have no overt evidence of neurological deficits, and are not requiring anti-epileptics or steroids to control their neurological symptoms; patients with known CNS metastases must have relevant CNS imaging performed approximately coincident with body imaging during response assessments
• PART B: The effects of ponatinib on the developing human fetus are unknown; for this reason women of child-bearing potential must have a negative urine or blood pregnancy test at screening for Part B; women of child-bearing potential and men must also have documented agreement to use adequate contraception (hormonal or barrier method of birth control; abstinence) from the time of screening until 30 days after the end of study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study, they should inform the treating physician immediately
• PART B: Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• PART A: Known EGFR mutation and/or ALK rearrangement in NSCLC with adenocarcinoma histology
• PART B: No previous treatment with a standard or investigational anti-cancer agent within predicted 5 half-lives of the agent; or 28 days whichever is the shorter; if the plasma half-life is not known or the previous therapy was a monoclonal antibody then a 28 day washout period will be considered as the default requirement
• PART B: No previous or current exposure to other FGFR inhibitors in the FGFR-selected cohorts, or RET inhibitors in the RET selected cohorts
• PART B: Prior radiotherapy to proposed target lesions is not permitted unless completed more than 4 weeks prior to treatment within the study and that there has been documented progression at these sites; radiotherapy to non-target lesions is permitted within 2 weeks of study entry provided all acute effects of the radiotherapy have resolved to =< grade 1
• PART B: History of allergic or severe reactions attributed to compounds of similar chemical or biologic composition to ponatinib
• PART B: Ponatinib is a substrate for cytochrome P450, family 3, subfamily A, polypeptide 4/5 (CYP3A4/5), concurrent use with potent CYP3A4/5 inhibitors or inducers should be undertaken with caution
• PART B: History of clinically significant bleeding disorder
• PART B: History of acute pancreatitis within 1 year of study or history of chronic pancreatitis
• PART B: Uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL)

• PART B: Uncontrolled intercurrent illness including, but not limited to:

  • Ongoing or active infection requiring intravenous antibiotics
  • Psychiatric illness/social situations that would limit compliance with study requirements
  • Congestive heart failure, unstable angina pectoris, or myocardial infarction within the 3 months prior to enrollment in part B of the study
  • History of clinically significant (as determined by the treating medical doctor [MD]) cardiac arrhythmia (atrial or ventricular)
• PART B: Patients who have had major surgery within 28 days prior to entering the study or those who have not recovered from adverse events > grade 1 relating to the surgery
• PART B: Pregnant or breastfeeding women
• PART B: Patients with inability to take oral medications, or, in the investigator's opinion, gastrointestinal conditions or abnormalities likely to influence the absorption of oral medications
• PART B: Concomitant use of medications known to be associated with torsades-de-pointes

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01935336
• Other Study ID Numbers: 13-2002.cc; NCI-2013-01644 ( Other Identifier: National Cancer Institute )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University of Colorado, Denver
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Colorado, Denver
• Original Study Sponsor: Same as current
• Collaborators: Ariad Pharmaceuticals

Investigators

• Principal Investigator: Ross D Camidge, MD, PhD; University of Colorado, Denver

• PRS Account: University of Colorado, Denver
• Verification Date: January 2022