Trial Outcomes & Findings for Study of Ponatinib in Patients With Lung Cancer Preselected Using Different Candidate Predictive Biomarkers (NCT NCT01935336)
NCT ID: NCT01935336
Last Updated: 2022-02-11
Results Overview
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-
Recruitment status
COMPLETED
Study phase
PHASE2
Target enrollment
171 participants
Primary outcome timeframe
Baseline
Results posted on
2022-02-11
Participant Flow
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.
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.
Participant milestones
| Measure |
Ponatinib SISH+/ISH+
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.
|
Ponatinib SISH+/ISH-
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.
|
Ponatinib SISH-/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 positive ISH
|
Ponatinib SISH-/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 Study
STARTED
|
6
|
3
|
47
|
66
|
|
Overall Study
Started Treatment
|
1
|
0
|
3
|
0
|
|
Overall Study
COMPLETED
|
0
|
0
|
0
|
0
|
|
Overall Study
NOT COMPLETED
|
6
|
3
|
47
|
66
|
Reasons for withdrawal
| Measure |
Ponatinib SISH+/ISH+
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.
|
Ponatinib SISH+/ISH-
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.
|
Ponatinib SISH-/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 positive ISH
|
Ponatinib SISH-/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 Study
Adverse Event
|
1
|
0
|
0
|
0
|
|
Overall Study
Progressive disease
|
5
|
3
|
47
|
66
|
Baseline Characteristics
Study of Ponatinib in Patients With Lung Cancer Preselected Using Different Candidate Predictive Biomarkers
Baseline characteristics by cohort
| Measure |
Ponatinib SISH+/ISH+
n=6 Participants
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.
|
Ponatinib SISH+/ISH-
n=3 Participants
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.
|
Ponatinib SISH-/ISH+
n=47 Participants
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
|
Ponatinib SISH-/ISH-
n=66 Participants
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
n=122 Participants
Total of all reporting groups
|
|---|---|---|---|---|---|
|
Age, Continuous
|
66.9 years
n=5 Participants
|
68.80 years
n=7 Participants
|
65.70 years
n=5 Participants
|
63.50 years
n=4 Participants
|
65.0 years
n=21 Participants
|
|
Sex: Female, Male
Female
|
1 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
26 Participants
n=5 Participants
|
33 Participants
n=4 Participants
|
61 Participants
n=21 Participants
|
|
Sex: Female, Male
Male
|
5 Participants
n=5 Participants
|
2 Participants
n=7 Participants
|
21 Participants
n=5 Participants
|
33 Participants
n=4 Participants
|
61 Participants
n=21 Participants
|
|
Smoking PY
|
37.5 Pack/year
n=5 Participants
|
57 Pack/year
n=7 Participants
|
30 Pack/year
n=5 Participants
|
30 Pack/year
n=4 Participants
|
30.73 Pack/year
n=21 Participants
|
|
Sites of metastases (soft tissue)
Yes
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
6 Participants
n=5 Participants
|
4 Participants
n=4 Participants
|
10 Participants
n=21 Participants
|
|
Sites of metastases (soft tissue)
No
|
6 Participants
n=5 Participants
|
3 Participants
n=7 Participants
|
41 Participants
n=5 Participants
|
62 Participants
n=4 Participants
|
112 Participants
n=21 Participants
|
|
Histology
Adenoca
|
2 Participants
n=5 Participants
|
2 Participants
n=7 Participants
|
28 Participants
n=5 Participants
|
48 Participants
n=4 Participants
|
80 Participants
n=21 Participants
|
|
Histology
Squamous
|
1 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
11 Participants
n=5 Participants
|
8 Participants
n=4 Participants
|
21 Participants
n=21 Participants
|
|
Histology
Small cell
|
3 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
8 Participants
n=5 Participants
|
10 Participants
n=4 Participants
|
21 Participants
n=21 Participants
|
|
KRAS
No
|
3 Participants
n=5 Participants
|
3 Participants
n=7 Participants
|
22 Participants
n=5 Participants
|
26 Participants
n=4 Participants
|
54 Participants
n=21 Participants
|
|
KRAS
Yes
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
16 Participants
n=5 Participants
|
28 Participants
n=4 Participants
|
44 Participants
n=21 Participants
|
|
KRAS
unevaluable
|
3 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
9 Participants
n=5 Participants
|
12 Participants
n=4 Participants
|
24 Participants
n=21 Participants
|
PRIMARY outcome
Timeframe: BaselinePopulation: 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).
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-
Outcome measures
| Measure |
SISH-
n=114 Participants
Less than four FGFR1 signals per nucleus (gene copy number) or FGFR1/CEP8 ratio ≥ 2.0
|
SISH+
n=9 Participants
At least four FGFR1 signals per nucleus (gene copy number) or FGFR1/CEP8 ratio ≥ 2.0
|
ISH-(<1%)
n=73 Participants
mRNA in situ hybridization with dot clusters per tumor \<1%
|
ISH+(>=1%)
n=53 Participants
mRNA in situ hybridization with dot clusters 1%=\<per tumor \<10%
|
ISH<20%
n=97 Participants
mRNA in situ hybridization with dot clusters 10%=\<per tumor \<20%
|
ISH>=20%
n=29 Participants
mRNA in situ hybridization with dot clusters 1per tumor \>=20%
|
|---|---|---|---|---|---|---|
|
Biomarker FGFR1 (ISH/SISH) Score (Part A)
|
0.93 gene copy number
Interval 0.87 to 0.97
|
0.07 gene copy number
Interval 0.03 to 0.134
|
0.579 gene copy number
Interval 0.488 to 0.667
|
0.42 gene copy number
Interval 0.333 to 0.512
|
0.77 gene copy number
Interval 0.686 to 0.84
|
0.23 gene copy number
Interval 0.16 to 0.31
|
PRIMARY outcome
Timeframe: BaselinePopulation: 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.
Overlapping frequency and its 95% CI between biomarkers among the screening patients and for different histologies will also be reported.
Outcome measures
| Measure |
SISH-
n=6 Participants
Less than four FGFR1 signals per nucleus (gene copy number) or FGFR1/CEP8 ratio ≥ 2.0
|
SISH+
n=3 Participants
At least four FGFR1 signals per nucleus (gene copy number) or FGFR1/CEP8 ratio ≥ 2.0
|
ISH-(<1%)
n=47 Participants
mRNA in situ hybridization with dot clusters per tumor \<1%
|
ISH+(>=1%)
n=66 Participants
mRNA in situ hybridization with dot clusters 1%=\<per tumor \<10%
|
ISH<20%
mRNA in situ hybridization with dot clusters 10%=\<per tumor \<20%
|
ISH>=20%
mRNA in situ hybridization with dot clusters 1per tumor \>=20%
|
|---|---|---|---|---|---|---|
|
Overlapping Frequency of FGFR1 (ISH/SISH) Biomarkers (Part A)
|
0.049 gene copy number
Interval 0.018 to 0.104
|
0.0246 gene copy number
Interval 0.005 to 0.07
|
0.385 gene copy number
Interval 0.299 to 0.478
|
0.541 gene copy number
Interval 0.448 to 0.632
|
—
|
—
|
PRIMARY outcome
Timeframe: From date of first dose until date of Disease Progression or death (up to 153 days), whichever occurred firstPopulation: 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.
Evaluated using Fisher's exact test with a descriptive p-value. Summarized using binomial proportions with 95% exact binomial confidence intervals.
Outcome measures
| Measure |
SISH-
n=1 Participants
Less than four FGFR1 signals per nucleus (gene copy number) or FGFR1/CEP8 ratio ≥ 2.0
|
SISH+
At least four FGFR1 signals per nucleus (gene copy number) or FGFR1/CEP8 ratio ≥ 2.0
|
ISH-(<1%)
n=3 Participants
mRNA in situ hybridization with dot clusters per tumor \<1%
|
ISH+(>=1%)
mRNA in situ hybridization with dot clusters 1%=\<per tumor \<10%
|
ISH<20%
mRNA in situ hybridization with dot clusters 10%=\<per tumor \<20%
|
ISH>=20%
mRNA in situ hybridization with dot clusters 1per tumor \>=20%
|
|---|---|---|---|---|---|---|
|
Objective Response Rate (ORR) Per RECIST v1.1 (Part B)
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
—
|
—
|
SECONDARY outcome
Timeframe: 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)Population: Due to the safety warning of Ponatinib and the adjusted inclusion and exclusion criteria, the study only treated 4 subjects in total.
Adverse events will be tabulated per participant, per organ, and per visit.
Outcome measures
| Measure |
SISH-
n=1 Participants
Less than four FGFR1 signals per nucleus (gene copy number) or FGFR1/CEP8 ratio ≥ 2.0
|
SISH+
At least four FGFR1 signals per nucleus (gene copy number) or FGFR1/CEP8 ratio ≥ 2.0
|
ISH-(<1%)
n=3 Participants
mRNA in situ hybridization with dot clusters per tumor \<1%
|
ISH+(>=1%)
mRNA in situ hybridization with dot clusters 1%=\<per tumor \<10%
|
ISH<20%
mRNA in situ hybridization with dot clusters 10%=\<per tumor \<20%
|
ISH>=20%
mRNA in situ hybridization with dot clusters 1per tumor \>=20%
|
|---|---|---|---|---|---|---|
|
Incidence of Adverse Events, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0
Grade 3
|
0 participants
|
—
|
2 participants
|
—
|
—
|
—
|
|
Incidence of Adverse Events, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0
Gr 3 fibrillation or febrile neutropenia or platelets
|
1 participants
|
—
|
2 participants
|
—
|
—
|
—
|
Adverse Events
Ponatinib SISH+/ISH+
Serious events: 1 serious events
Other events: 1 other events
Deaths: 0 deaths
Ponatinib SISH+/ISH-
Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths
Ponatinib SISH-/ISH+
Serious events: 2 serious events
Other events: 2 other events
Deaths: 0 deaths
Ponatinib SISH-/ISH-
Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Ponatinib SISH+/ISH+
n=1 participants at risk
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.
|
Ponatinib SISH+/ISH-
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.
|
Ponatinib SISH-/ISH+
n=3 participants at risk
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
|
Ponatinib SISH-/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
|
|---|---|---|---|---|
|
Gastrointestinal disorders
Grade 3 AE
|
100.0%
1/1 • Number of events 1 • During the first year post treatment
The number at risk for all-cause mortality is 4 The number at risk for SAE was 4. There were 75% SAEs.
|
—
0/0 • During the first year post treatment
The number at risk for all-cause mortality is 4 The number at risk for SAE was 4. There were 75% SAEs.
|
66.7%
2/3 • Number of events 2 • During the first year post treatment
The number at risk for all-cause mortality is 4 The number at risk for SAE was 4. There were 75% SAEs.
|
—
0/0 • During the first year post treatment
The number at risk for all-cause mortality is 4 The number at risk for SAE was 4. There were 75% SAEs.
|
Other adverse events
| Measure |
Ponatinib SISH+/ISH+
n=1 participants at risk
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.
|
Ponatinib SISH+/ISH-
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.
|
Ponatinib SISH-/ISH+
n=3 participants at risk
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
|
Ponatinib SISH-/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
|
|---|---|---|---|---|
|
Blood and lymphatic system disorders
Grade 2 hypertension
|
100.0%
1/1 • Number of events 1 • During the first year post treatment
The number at risk for all-cause mortality is 4 The number at risk for SAE was 4. There were 75% SAEs.
|
—
0/0 • During the first year post treatment
The number at risk for all-cause mortality is 4 The number at risk for SAE was 4. There were 75% SAEs.
|
66.7%
2/3 • Number of events 3 • During the first year post treatment
The number at risk for all-cause mortality is 4 The number at risk for SAE was 4. There were 75% SAEs.
|
—
0/0 • During the first year post treatment
The number at risk for all-cause mortality is 4 The number at risk for SAE was 4. There were 75% SAEs.
|
|
Blood and lymphatic system disorders
Grade 2 thrombocytopenia
|
100.0%
1/1 • Number of events 1 • During the first year post treatment
The number at risk for all-cause mortality is 4 The number at risk for SAE was 4. There were 75% SAEs.
|
—
0/0 • During the first year post treatment
The number at risk for all-cause mortality is 4 The number at risk for SAE was 4. There were 75% SAEs.
|
0.00%
0/3 • During the first year post treatment
The number at risk for all-cause mortality is 4 The number at risk for SAE was 4. There were 75% SAEs.
|
—
0/0 • During the first year post treatment
The number at risk for all-cause mortality is 4 The number at risk for SAE was 4. There were 75% SAEs.
|
Additional Information
Dr. Ross Camidge
U of Colorado, Division of Medical Oncology. Anschutz Medical Campus
Phone: 7208480300
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place