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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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:
Collaborator:
Ariad Pharmaceuticals
Information provided by (Responsible Party):
University of Colorado, Denver

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions 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
Enrollment 171
Recruitment Details

This is a biomarker driven clinical trial with prescreening for 4 molecular cohorts based on ISH and SISH positivity- FGFR1 ISH+/SISH+, FGFR1 ISH+/SISH-, FGFR1 ISH-/SISH+, and FGFR1 ISH-/SISH-; with the provision of testing for RET rearrangement in the double negative cohort.

From Sep2013 to Nov2017, 171 patient samples were prescreened and resulted in 122 samples that had both SISH and ISH scores reportable. 4 of those patients signed main consent and were enrolled to treatment with ponatinib.
Pre-assignment Details Tissue samples from patients were prescreened for markers. 171 samples were prescreened. Of these samples, biomarker results were obtained for 122 samples. Of the patients, from which these samples were derived, 4 patients were then enrolled on the study intervention, allocated to different arms based on their biomarker results. Unfortunately, due to poor tolerability and safety concerns regarding ponatinib after treating the first 4 patients, the trial stopped.
Arm/Group Title Ponatinib SISH+/ISH+ Ponatinib SISH+/ISH- Ponatinib SISH-/ISH+ Ponatinib SISH-/ISH-
Hide Arm/Group Description

The pre-defined cutpoint for FGFR1 amplification (SISH+) was an average of at least four FGFR1 signals per nucleus (gene copy number) or FGFR1/CEP8 ratio ≥ 2.0.

mRNA in situ hybridization (ISH) was performed on formalin-fixed paraffin embedded (FFPE) tumor tissue using the RNA scope 2.0 assay system. ISH scores were generated and recorded using the following scoring system at 200 × magnification: 0, no staining; 1, one to 3 dots per tumor cell; 2, 4 to 10 dots per tumor cell; 3, more than 10 dots per cell or presence of dot clusters in ≥1% and < 10% tumor cells; 4, ≥ 10% tumor cells with dot clusters as per the RNA scope system scoring guidelines.18 The pre-defined cutpoint for FGFR1 ISH positivity was a score of 3 or 4 per this scoring system.

Please see details in Ponatinib SISH+/ISH+ for the definition of SISH positivity and ISH positivity.

Subjects in this group are those with SISH positive and ISH negative.

Please see details in Ponatinib SISH+/ISH+ for the definition of SISH positivity and ISH positivity.

Subjects in this group with a negative SISH and a positive ISH

Please see details in Ponatinib SISH+/ISH+ for the definition of SISH positivity and ISH positivity.

Subjects in this group with a negative SISH and a negative ISH
Period Title: Overall Study
Started 6 [1] 3 [2] 47 [3] 66 [2]
Started Treatment 1 0 3 0
Completed 0 0 0 0
Not Completed 6 3 47 66
Reason Not Completed
Adverse Event             1             0             0             0
Progressive disease             5             3             47             66
[1]
Only one subject was treated due to the black box warning RE: ponatinib-associated vascular issues. The protocol was modified with additional inclusion and exclusion criteria, which severely limited the number of cases treated with the drug
[2]
no subjects were treated in this arm
[3]
Only three subjects were treated due to the black box warning RE: ponatinib-associated vascular issues. The protocol was modified with additional inclusion and exclusion criteria, which severely limited the number of cases treated with the drug
Arm/Group Title Ponatinib SISH+/ISH+ Ponatinib SISH+/ISH- Ponatinib SISH-/ISH+ Ponatinib SISH-/ISH- Total
Hide Arm/Group Description

The pre-defined cutpoint for FGFR1 amplification (SISH+) was an average of at least four FGFR1 signals per nucleus (gene copy number) or FGFR1/CEP8 ratio ≥ 2.0.

mRNA in situ hybridization (ISH) was performed on formalin-fixed paraffin embedded (FFPE) tumor tissue using the RNA scope 2.0 assay system. ISH scores were generated and recorded using the following scoring system at 200 × magnification: 0, no staining; 1, one to 3 dots per tumor cell; 2, 4 to 10 dots per tumor cell; 3, more than 10 dots per cell or presence of dot clusters in ≥1% and < 10% tumor cells; 4, ≥ 10% tumor cells with dot clusters as per the RNA scope system scoring guidelines.18 The pre-defined cutpoint for FGFR1 ISH positivity was a score of 3 or 4 per this scoring system.

Please see details in Ponatinib SISH+/ISH+ for the definition of SISH positivity and ISH positivity.

Subjects in this group are those with SISH positive and ISH negative.

Please see details in Ponatinib SISH+/ISH+ for the definition of SISH positivity and ISH positivity.

Subjects in this group with a negative SISH and a positive ISH

Please see details in Ponatinib SISH+/ISH+ for the definition of SISH positivity and ISH positivity.

Subjects in this group with a negative SISH and a negative ISH

 Total of all reporting groups
Overall Number of Baseline Participants 6 3 47 66 122
Hide Baseline Analysis Population Description
171 subjects were pre-screen consented to request and submit tissue for ISH and SISH scoring. 122 of 171 subjects received ISH/SISH results and of those 122 subjects who received ISH/SISH results, 4 were main consented and enrolled to actual treatment with ponatinib.
Age, Continuous  
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 6 participants 3 participants 47 participants 66 participants 122 participants
66.9
(64.88 to 72.38)
68.80
(67.05 to 69.15)
65.70
(57.50 to 72.55)
63.50
(58.05 to 70.70)
65.0
(58.05 to 72.45)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 3 participants 47 participants 66 participants 122 participants
Female 1 1 26 33 61
Male 5 2 21 33 61
Smoking PY  
Median (Inter-Quartile Range)
Unit of measure:  Pack/year
Number Analyzed 6 participants 3 participants 47 participants 66 participants 122 participants
37.5
(31.35 to 51.25)
57
(45 to 68.5)
30
(17.5 to 50.0)
30
(9 to 42.94)
30.73
(11.3 to 45)
Sites of metastases (soft tissue)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 3 participants 47 participants 66 participants 122 participants
Yes
0
   0.0%
0
   0.0%
6
  12.8%
4
   6.1%
10
   8.2%
No
6
 100.0%
3
 100.0%
41
  87.2%
62
  93.9%
112
  91.8%
Histology  
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 6 participants 3 participants 47 participants 66 participants 122 participants
Adenoca
2
  33.3%
2
  66.7%
28
  59.6%
48
  72.7%
80
  65.6%
Squamous
1
  16.7%
1
  33.3%
11
  23.4%
8
  12.1%
21
  17.2%
Small cell
3
  50.0%
0
   0.0%
8
  17.0%
10
  15.2%
21
  17.2%
KRAS  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 3 participants 47 participants 66 participants 122 participants
No
3
  50.0%
3
 100.0%
22
  46.8%
26
  39.4%
54
  44.3%
Yes
0
   0.0%
0
   0.0%
16
  34.0%
28
  42.4%
44
  36.1%
unevaluable
3
  50.0%
0
   0.0%
9
  19.1%
12
  18.2%
24
  19.7%
1.Primary Outcome
Title Biomarker FGFR1 (ISH/SISH) Score (Part A)
Hide Description 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-
Time Frame Baseline
Hide Outcome Measure Data
Hide Analysis Population Description
171 cases were prescreened. Among them, 122 cases had both SISH and ISH scores reported, one case had only SISH and four cases had only ISH reported, and 44 cases lacked both SISH and ISH scores, resulting in 123 cases with SISH and 126 cases with ISH. Please note that the 126 cases with ISH scores were displayed in two different ways, one was based on ISH<1% vs >+1% (columns 3 and 4 above), and the other was based on ISH<20% vs >=20% (columns 5 and 6).
Arm/Group Title SISH- SISH+ ISH-(<1%) ISH+(>=1%) ISH<20% ISH>=20%
Hide Arm/Group Description:
Less than four FGFR1 signals per nucleus (gene copy number) or FGFR1/CEP8 ratio ≥ 2.0
At least four FGFR1 signals per nucleus (gene copy number) or FGFR1/CEP8 ratio ≥ 2.0
mRNA in situ hybridization with dot clusters per tumor <1%
mRNA in situ hybridization with dot clusters 1%=<per tumor <10%
mRNA in situ hybridization with dot clusters 10%=<per tumor <20%
mRNA in situ hybridization with dot clusters 1per tumor >=20%
Overall Number of Participants Analyzed 114 9 73 53 97 29
Mean (95% Confidence Interval)
Unit of Measure: gene copy number
0.93
(0.87 to 0.97)
0.07
(0.03 to 0.134)
0.579
(0.488 to 0.667)
0.42
(0.333 to 0.512)
0.77
(0.686 to 0.84)
0.23
(0.16 to 0.31)
2.Primary Outcome
Title Overlapping Frequency of FGFR1 (ISH/SISH) Biomarkers (Part A)
Hide Description Overlapping frequency and its 95% CI between biomarkers among the screening patients and for different histologies will also be reported.
Time Frame Baseline
Hide Outcome Measure Data
Hide Analysis Population Description
171 subjects were pre-screen consented to request and submit tissue for ISH and SISH scoring. 122 of 171 subjects received ISH/SISH results and of those 122 subjects who received ISH/SISH results, 4 were enrolled to actual treatment with ponatinib. The number reported here are the eligible number of subjects in each pre-defined category.
Arm/Group Title Ponatinib SISH+/ISH+ Ponatinib SISH+/ISH- Ponatinib SISH-/ISH+ Ponatinib SISH-/ISH-
Hide Arm/Group Description:

The pre-defined cutpoint for FGFR1 amplification (SISH+) was an average of at least four FGFR1 signals per nucleus (gene copy number) or FGFR1/CEP8 ratio ≥ 2.0.

mRNA in situ hybridization (ISH) was performed on formalin-fixed paraffin embedded (FFPE) tumor tissue using the RNA scope 2.0 assay system. ISH scores were generated and recorded using the following scoring system at 200 × magnification: 0, no staining; 1, one to 3 dots per tumor cell; 2, 4 to 10 dots per tumor cell; 3, more than 10 dots per cell or presence of dot clusters in ≥1% and < 10% tumor cells; 4, ≥ 10% tumor cells with dot clusters as per the RNA scope system scoring guidelines.18 The pre-defined cutpoint for FGFR1 ISH positivity was a score of 3 or 4 per this scoring system.

Please see details in Ponatinib SISH+/ISH+ for the definition of SISH positivity and ISH positivity.

Subjects in this group are those with SISH positive and ISH negative.

Please see details in Ponatinib SISH+/ISH+ for the definition of SISH positivity and ISH positivity.

Subjects in this group with a negative SISH and a positive ISH

Please see details in Ponatinib SISH+/ISH+ for the definition of SISH positivity and ISH positivity.

Subjects in this group with a negative SISH and a negative ISH
Overall Number of Participants Analyzed 6 3 47 66
Mean (95% Confidence Interval)
Unit of Measure: gene copy number
0.049
(0.018 to 0.104)
0.0246
(0.005 to 0.070)
0.385
(0.299 to 0.478)
0.541
(0.448 to 0.632)
3.Primary Outcome
Title Objective Response Rate (ORR) Per RECIST v1.1 (Part B)
Hide Description Evaluated using Fisher's exact test with a descriptive p-value. Summarized using binomial proportions with 95% exact binomial confidence intervals.
Time Frame From date of first dose until date of Disease Progression or death (up to 153 days), whichever occurred first
Hide Outcome Measure Data
Hide Analysis Population Description
A total of 4 subjects were treated, where the 3 SISH-/ISH+ all with RET-, due to the safety concern of ponatinib and the change of inclusion and exclusion criteria.
Arm/Group Title Ponatinib SISH+/ISH+ Ponatinib SISH+/ISH- Ponatinib SISH-/ISH+ Ponatinib SISH-/ISH-
Hide Arm/Group Description:

The pre-defined cutpoint for FGFR1 amplification (SISH+) was an average of at least four FGFR1 signals per nucleus (gene copy number) or FGFR1/CEP8 ratio ≥ 2.0.

mRNA in situ hybridization (ISH) was performed on formalin-fixed paraffin embedded (FFPE) tumor tissue using the RNA scope 2.0 assay system. ISH scores were generated and recorded using the following scoring system at 200 × magnification: 0, no staining; 1, one to 3 dots per tumor cell; 2, 4 to 10 dots per tumor cell; 3, more than 10 dots per cell or presence of dot clusters in ≥1% and < 10% tumor cells; 4, ≥ 10% tumor cells with dot clusters as per the RNA scope system scoring guidelines.18 The pre-defined cutpoint for FGFR1 ISH positivity was a score of 3 or 4 per this scoring system.

Please see details in Ponatinib SISH+/ISH+ for the definition of SISH positivity and ISH positivity.

Subjects in this group are those with SISH positive and ISH negative.

Please see details in Ponatinib SISH+/ISH+ for the definition of SISH positivity and ISH positivity.

Subjects in this group with a negative SISH and a positive ISH

Please see details in Ponatinib SISH+/ISH+ for the definition of SISH positivity and ISH positivity.

Subjects in this group with a negative SISH and a negative ISH
Overall Number of Participants Analyzed 1 0 3 0
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
 0
0
   0.0%
 0
4.Secondary Outcome
Title Incidence of Adverse Events, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0
Hide Description Adverse events will be tabulated per participant, per organ, and per visit.
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)
Hide Outcome Measure Data
Hide Analysis Population Description
Due to the safety warning of Ponatinib and the adjusted inclusion and exclusion criteria, the study only treated 4 subjects in total.
Arm/Group Title Ponatinib SISH+/ISH+ Ponatinib SISH+/ISH- Ponatinib SISH-/ISH+ Ponatinib SISH-/ISH-
Hide Arm/Group Description:

The pre-defined cutpoint for FGFR1 amplification (SISH+) was an average of at least four FGFR1 signals per nucleus (gene copy number) or FGFR1/CEP8 ratio ≥ 2.0.

mRNA in situ hybridization (ISH) was performed on formalin-fixed paraffin embedded (FFPE) tumor tissue using the RNA scope 2.0 assay system. ISH scores were generated and recorded using the following scoring system at 200 × magnification: 0, no staining; 1, one to 3 dots per tumor cell; 2, 4 to 10 dots per tumor cell; 3, more than 10 dots per cell or presence of dot clusters in ≥1% and < 10% tumor cells; 4, ≥ 10% tumor cells with dot clusters as per the RNA scope system scoring guidelines.18 The pre-defined cutpoint for FGFR1 ISH positivity was a score of 3 or 4 per this scoring system.

Please see details in Ponatinib SISH+/ISH+ for the definition of SISH positivity and ISH positivity.

Subjects in this group are those with SISH positive and ISH negative.

Please see details in Ponatinib SISH+/ISH+ for the definition of SISH positivity and ISH positivity.

Subjects in this group with a negative SISH and a positive ISH

Please see details in Ponatinib SISH+/ISH+ for the definition of SISH positivity and ISH positivity.

Subjects in this group with a negative SISH and a negative ISH
Overall Number of Participants Analyzed 1 0 3 0
Measure Type: Number
Unit of Measure: participants
Grade 3 0 2
Gr 3 fibrillation or febrile neutropenia or platelets 1 2
Time Frame During the first year post treatment
Adverse Event Reporting Description The number at risk for all-cause mortality is 4 The number at risk for SAE was 4. There were 75% SAEs.
 
Arm/Group Title Ponatinib SISH+/ISH+ Ponatinib SISH+/ISH- Ponatinib SISH-/ISH+ Ponatinib SISH-/ISH-
Hide Arm/Group Description

The pre-defined cutpoint for FGFR1 amplification (SISH+) was an average of at least four FGFR1 signals per nucleus (gene copy number) or FGFR1/CEP8 ratio ≥ 2.0.

mRNA in situ hybridization (ISH) was performed on formalin-fixed paraffin embedded (FFPE) tumor tissue using the RNA scope 2.0 assay system. ISH scores were generated and recorded using the following scoring system at 200 × magnification: 0, no staining; 1, one to 3 dots per tumor cell; 2, 4 to 10 dots per tumor cell; 3, more than 10 dots per cell or presence of dot clusters in ≥1% and < 10% tumor cells; 4, ≥ 10% tumor cells with dot clusters as per the RNA scope system scoring guidelines.18 The pre-defined cutpoint for FGFR1 ISH positivity was a score of 3 or 4 per this scoring system.

Please see details in Ponatinib SISH+/ISH+ for the definition of SISH positivity and ISH positivity.

Subjects in this group are those with SISH positive and ISH negative.

Please see details in Ponatinib SISH+/ISH+ for the definition of SISH positivity and ISH positivity.

Subjects in this group with a negative SISH and a positive ISH

Please see details in Ponatinib SISH+/ISH+ for the definition of SISH positivity and ISH positivity.

Subjects in this group with a negative SISH and a negative ISH
All-Cause Mortality
Ponatinib SISH+/ISH+ Ponatinib SISH+/ISH- Ponatinib SISH-/ISH+ Ponatinib SISH-/ISH-
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/1 (0.00%)      0/0      0/3 (0.00%)      0/0    
Hide Serious Adverse Events
Ponatinib SISH+/ISH+ Ponatinib SISH+/ISH- Ponatinib SISH-/ISH+ Ponatinib SISH-/ISH-
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/1 (100.00%)      0/0      2/3 (66.67%)      0/0    
Gastrointestinal disorders         
Grade 3 AE † 1 [1]  1/1 (100.00%)  1 /0  2/3 (66.67%)  2 /0 
1
Term from vocabulary, MedDRA 10.0
†
Indicates events were collected by systematic assessment
[1]
Febrile neutropenia, Bowel perforation, Hyponatremia
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Ponatinib SISH+/ISH+ Ponatinib SISH+/ISH- Ponatinib SISH-/ISH+ Ponatinib SISH-/ISH-
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/1 (100.00%)      0/0      2/3 (66.67%)      0/0    
Blood and lymphatic system disorders         
Grade 2 hypertension † 1  1/1 (100.00%)  1 0/0  0 2/3 (66.67%)  3 0/0  0
Grade 2 thrombocytopenia † 1  1/1 (100.00%)  1 0/0  0 0/3 (0.00%)  0 0/0  0
1
Term from vocabulary, MedDRA 10.0
†
Indicates events were collected by systematic assessment
Due to poor tolerability and safety concerns regarding ponatinib after treating the first few patients, the study did not reach its accrual target (N~70) for the treatment portion of this study and could not confirm or refute the null hypothesis (needed a minimum of 12 patients treated). This study prescreened a more heterogeneous population. As a result, all four patients that were enrolled onto the ponatinib treatment arm had either squamous or poorly differentiated lung cancer.
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Ross Camidge
Organization: U of Colorado, Division of Medical Oncology. Anschutz Medical Campus
Phone: 7208480300
EMail: ross.camidge@cuanschutz.edu
Layout table for additonal information
Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT01935336    
Other Study ID Numbers: 13-2002.cc
NCI-2013-01644 ( Other Identifier: National Cancer Institute )
First Submitted: August 27, 2013
First Posted: September 5, 2013
Results First Submitted: April 5, 2021
Results First Posted: February 11, 2022
Last Update Posted: February 11, 2022