This is an open-label, multi-center, single arm phase II trial, with a two-stage design, to evaluate the activity and safety of ABT-199 single agent in patients with BCL-2 pos R/R PTCL-NOS, AITL, TFH.
A pre-screening evaluation of immunohistochemical positivity of BCL-2 will be performed in the relapse biopsy, if available, or otherwise in the initial biopsy. BCL-2 evaluation will be centralized (FIL Laboratories). Only patients with a percentage of BCL-2 positive tumor cells ≥ 25% will be included onto the study. Patients will receive ABT-199 until disease progression, unacceptable toxicity, withdrawal of consent and/or the investigator determines that further therapy is not in the patient's best interest. The primary objective of the study is ORR which will be evaluated after 3 cycles of treatment.
ABT-199 will be administered orally at the dose of 800 mg once daily. Patients will receive ABT-199 until disease progression, unacceptable toxicity, withdrawal of consent and/or the investigator determines that further therapy is not in the patient's best interest (e.g., due to non-compliance, toxicity...) Response evaluation will be performed initially after 3 cycles from the beginning of treatment with ABT-199 (Response Assessment 1) and then every 3 cycles during the first 12 cycles, every 4 cycles from cycle 13 to 24; for those patients still on therapy after 24 cycles, the response evaluation, after this time, will be performed every 6 cycles.
Response will be evaluated according to the Lugano 2014 classification.
TLS is an important identified risk for ABT-199 in oncology studies, especially in CLL. Since there are no available data on the risk of TLS in PTCL, the risk of TLS development should be closely monitored during the study.
TLS prophylaxis includes:
1. ABT-199 will be administered according the following ramp up:
* week 1 day 1: 20 mg
* week 1 day 2-3: 50 mg
* week 1 day 4-7: 100 mg
* week 2: 200 mg
* week 3: 400 mg
* week 4 and following: 800 mg
2. Hospitalization and monitoring of the subject should occur for a minimum of 72 hours after the initial dose. Discharge of the subject is dependent upon review of chemistry labs 72 hours after the first dose of ABT-199
3. IV hydration (150 cc/hr, as tolerable) must be started upon admission and continued during hospitalization at least for 72 hours after the initial dose of ABT-199. Urine output must be monitored
4. Allopurinol 300 mg daily to be initiated 3 days before treatment and continued for up to 5 weeks based on the ongoing risk of TLS development. Subjects allergic to allopurinol must use another anti-hypeuricemic drug. Consider use of rasburicase if subjects baseline uric acid level is elevated
5. The investigator decision to proceed with ABT-199 treatment initiation and subsequent ramp up will be after having evaluated the normal value of the following biochemistry (potassium, uric acid, phosphorus, calcium and creatinine).
Biohemistry labs (potassium, uric acid, phosphorus, calcium and creatinine) must be performed as follow:
* week 1 (ABT-199 dose from 20 to 100 mg/daily): at timepoints 0 (pre-dose, within 4 hours from ABT-199 administration), 6-8, 24, 48, 72, 96 hours after the first dose of ABT-199. Day 2 dose should not be administered until the 24 hours post-dose labs are reviewed by the investigator;
* week 2 (ABT-199 dose 200 mg/daily): at timepoints 0 (pre-dose, with-in 4 hours from ABT-199 administration), 6-8, 24 hours after. Day 2 dose should not be administered until the 24 hours post-dose labs are reviewed by the investigator;
* week 3 (ABT-199 dose 400 mg/daily): at timepoints 0 (pre-dose, with-in 4 hours from ABT-199 administration), 6-8, 24 hours after. Day 2 dose should not be administered until the 24 hours post-dose labs are reviewed by the investigator;
* week 4 (ABT-199 dose 800 mg/daily): at timepoints 0 (pre-dose, with-in 4 hours from ABT-199 administration), 6-8, 24 hours after. Day 2 dose should not be administered until the 24 hours post-dose labs are reviewed by the investigator Nephrology (or other acute dialysis service) must be consulted/contacted on admission (per institutional standards to ensure emergency dialysis is available).
The efficacy interim analysis will be performed after enrollment of 18 patients. It is to be planned a stop in recruitment of at least 3 months to have the results of response assessment. The primary efficacy analysis will consist of an estimate of ORR on the efficacy population after the first 3 cycles of therapy, with 90% confidence intervals (according to 1-sided alpha error of 0.05). To proceed to the second stage, the minimum number of patients with an ORR is 3/18.
