Trial Outcomes & Findings for Pharmacokinetic & Pharmacodynamic Study of ABT-751 With Carboplatin in Patients With Advanced Lung Cancer (NCT NCT00735878)

Results Overview

The maximum tolerated dose (MTD) of escalating ABT-751 in combination with fixed dose Carboplatin AUC 6 in patients with advanced non small cell lung cancer (NSCLC). Initially, 1 patient will be enrolled in dose level 1. If the patient experiences a Gr 2 toxicity, additional 2 patients will be enrolled at the dose level. If 1 of the 3 patients experience a Gr 3 toxicity or higher the cohort will be expanded to 6 patients. However, if 1 patient completes one cycle at the assigned dose regimen without a Gr 2 toxicity, enrollment in the next cohort (dose level 2) can begin. The rapid dose escalation scheme will apply to cohorts 1 through 3.

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

20 participants

Primary outcome timeframe

21 Days (end of cycle 1)

Results posted on

2018-10-12

Participant Flow

Participants will be recruited from inpatient and outpatient populations at DHMC and through physician referrals.

Participant milestones

Participant milestones
Measure	100 mg Maximum Tolerated Dose Determination Phase	125 mg Maximum Tolerated Dose Determination Phase	150 mg Maximum Tolerated Dose Determination Phase
Phase I- Dose Determination STARTED	1	7	5
Phase I- Dose Determination COMPLETED	1	7	4
Phase I- Dose Determination NOT COMPLETED	0	0	1
Phase II- Determined Dose STARTED	0	7	0
Phase II- Determined Dose COMPLETED	0	7	0
Phase II- Determined Dose NOT COMPLETED	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	100 mg Maximum Tolerated Dose Determination Phase	125 mg Maximum Tolerated Dose Determination Phase	150 mg Maximum Tolerated Dose Determination Phase
Phase I- Dose Determination Withdrawal by Subject	0	0	1

Baseline Characteristics

Pharmacokinetic & Pharmacodynamic Study of ABT-751 With Carboplatin in Patients With Advanced Lung Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	100 mg n=1 Participants Maximum Tolerated Dose Determination Phase	125 mg n=14 Participants Maximum Tolerated Dose Determination Phase	150 mg n=5 Participants Maximum Tolerated Dose Determination Phase	Total n=20 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	1 Participants n=5 Participants	9 Participants n=7 Participants	3 Participants n=5 Participants	13 Participants n=4 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	5 Participants n=7 Participants	2 Participants n=5 Participants	7 Participants n=4 Participants
Age, Continuous	63 years n=5 Participants	62 years STANDARD_DEVIATION 7.65 • n=7 Participants	63 years STANDARD_DEVIATION 9.28 • n=5 Participants	62 years STANDARD_DEVIATION 8.28 • n=4 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	7 Participants n=4 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	11 Participants n=7 Participants	1 Participants n=5 Participants	13 Participants n=4 Participants
Region of Enrollment United States	1 participants n=5 Participants	14 participants n=7 Participants	5 participants n=5 Participants	20 participants n=4 Participants

PRIMARY outcome

Timeframe: 21 Days (end of cycle 1)

The maximum tolerated dose (MTD) of escalating ABT-751 in combination with fixed dose Carboplatin AUC 6 in patients with advanced non small cell lung cancer (NSCLC). Initially, 1 patient will be enrolled in dose level 1. If the patient experiences a Gr 2 toxicity, additional 2 patients will be enrolled at the dose level. If 1 of the 3 patients experience a Gr 3 toxicity or higher the cohort will be expanded to 6 patients. However, if 1 patient completes one cycle at the assigned dose regimen without a Gr 2 toxicity, enrollment in the next cohort (dose level 2) can begin. The rapid dose escalation scheme will apply to cohorts 1 through 3.

Outcome measures

Outcome measures
Measure	Group 1/ Dose Escalating ABT-751 in Combination With Carboplat n=13 Participants Oral dose escalating of ABT-871 given BID on Day 1 of each cycle for 7 days in combination with Carboplatin given on a 21-day schedule. There will be up to 7 Cohorts(Dose Levels) from 100 to 200 mg/m2 of ABT-751 mg BID with Carboplatin AUC 4.5 for the first two cohorts, and AUC 6 for the remaining.	Group 2/ Phase II Phase 2 participants treated at MTD.
Maximum Tolerated Dose (MTD) of ABT-751 in Combination With Carboplatin	125 mg of ABT-751	—

PRIMARY outcome

Timeframe: 42 days (end of cycle 2)

The effectiveness of the combination with ABT-751 and carboplatin in patients with advanced NSCLC as measured by objective response rate. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) for target lesions and assessed by CT or MRI: Complete Response (CR), The disappearance of all known disease determined by two observations not less than four weeks apart.; Partial Response (PR), At least a 30% or more decrease in total tumor load of the lesions that have been measured to determine the effect of therapy by two observations not less than four weeks apart.; Overall Response (OR) = CR + PR

Outcome measures

Outcome measures
Measure	Group 1/ Dose Escalating ABT-751 in Combination With Carboplat n=13 Participants Oral dose escalating of ABT-871 given BID on Day 1 of each cycle for 7 days in combination with Carboplatin given on a 21-day schedule. There will be up to 7 Cohorts(Dose Levels) from 100 to 200 mg/m2 of ABT-751 mg BID with Carboplatin AUC 4.5 for the first two cohorts, and AUC 6 for the remaining.	Group 2/ Phase II Phase 2 participants treated at MTD.
Objective Response Rate of Participants Using A Combination of ABT-751 and Carboplatin	13 Participants	—

PRIMARY outcome

Timeframe: from the start of the study until the last subject dies (up to 100 weeks)

Population: 12 Participants were enrolled into the phase 1 portion of the tiral and later 8 more patients were enrolled for a total of 20 analyzed patients.

Median overall survival using the Kaplan Meier method

Outcome measures

Outcome measures
Measure	Group 1/ Dose Escalating ABT-751 in Combination With Carboplat n=20 Participants Oral dose escalating of ABT-871 given BID on Day 1 of each cycle for 7 days in combination with Carboplatin given on a 21-day schedule. There will be up to 7 Cohorts(Dose Levels) from 100 to 200 mg/m2 of ABT-751 mg BID with Carboplatin AUC 4.5 for the first two cohorts, and AUC 6 for the remaining.	Group 2/ Phase II Phase 2 participants treated at MTD.
The Median Survival in the Study Population	11.7 months Interval 5.9 to 27.0	—

SECONDARY outcome

Timeframe: Randomization to maximum tolerated dose confirmed

Population: Data were not collected. The PK analysis was not performed at the request of financial sponsor.

The pharmacokinetic profile of ABT-751 given in combination with carboplatin in a subset of patients, treated at the MTD or recommended doses for Phase 2.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: pretreatment (Day 0) and patient paired post- treatment (Days 4,8, 22) buccal swabs.

Population: A subset of patients treated at the recommended Phase II dose from Phase II/Group 2

Cyclin D1 levels were evaluated by immunoblot analyses of pretreatment (day 0) and paired posttreatment (day 4, 8 and 22) buccal swabs.

Outcome measures

Outcome measures
Measure	Group 1/ Dose Escalating ABT-751 in Combination With Carboplat n=6 Participants Oral dose escalating of ABT-871 given BID on Day 1 of each cycle for 7 days in combination with Carboplatin given on a 21-day schedule. There will be up to 7 Cohorts(Dose Levels) from 100 to 200 mg/m2 of ABT-751 mg BID with Carboplatin AUC 4.5 for the first two cohorts, and AUC 6 for the remaining.	Group 2/ Phase II Phase 2 participants treated at MTD.
Number of Patients With Buccal Cells Demonstrating a Decline in Cyclin D1 Decline in Cyclin D1 expression on Day 4	0 participants	—
Number of Patients With Buccal Cells Demonstrating a Decline in Cyclin D1 Decline in Cyclin D1 expression on Day 8	3 participants	—
Number of Patients With Buccal Cells Demonstrating a Decline in Cyclin D1 Decline in Cyclin D1 expression on Day 22	4 participants	—

Adverse Events

100 mg

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

125 mg

Serious events: 1 serious events

Other events: 12 other events

Deaths: 0 deaths

150 mg

Serious events: 1 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	100 mg n=1 participants at risk Maximum Tolerated Dose Determination Phase	125 mg n=14 participants at risk Maximum Tolerated Dose Determination Phase	150 mg n=5 participants at risk Maximum Tolerated Dose Determination Phase
Blood and lymphatic system disorders Neutropenia	0.00% 0/1 • 4 years	0.00% 0/14 • 4 years	20.0% 1/5 • Number of events 1 • 4 years
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/1 • 4 years	7.1% 1/14 • Number of events 1 • 4 years	0.00% 0/5 • 4 years

Other adverse events

Other adverse events
Measure	100 mg n=1 participants at risk Maximum Tolerated Dose Determination Phase	125 mg n=14 participants at risk Maximum Tolerated Dose Determination Phase	150 mg n=5 participants at risk Maximum Tolerated Dose Determination Phase
Gastrointestinal disorders Constipation	0.00% 0/1 • 4 years	35.7% 5/14 • Number of events 5 • 4 years	40.0% 2/5 • Number of events 2 • 4 years
Gastrointestinal disorders Ileus	0.00% 0/1 • 4 years	0.00% 0/14 • 4 years	40.0% 2/5 • Number of events 2 • 4 years
Nervous system disorders Neuropathy	0.00% 0/1 • 4 years	0.00% 0/14 • 4 years	40.0% 2/5 • Number of events 2 • 4 years
General disorders Fatigue	0.00% 0/1 • 4 years	21.4% 3/14 • Number of events 3 • 4 years	60.0% 3/5 • Number of events 3 • 4 years
Blood and lymphatic system disorders Hypokalemia	0.00% 0/1 • 4 years	14.3% 2/14 • Number of events 2 • 4 years	40.0% 2/5 • Number of events 2 • 4 years
Blood and lymphatic system disorders Thrombocytopenia	100.0% 1/1 • Number of events 1 • 4 years	14.3% 2/14 • Number of events 2 • 4 years	40.0% 2/5 • Number of events 2 • 4 years

Additional Information

Konstantin H. Dragnev, MD

Dartmouth-Hitchcock Medical Center (DHMC)

Phone: (603) 650-6344

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place