Use of Venetoclax as Single Agent in Patients With Relapsed/Refractory BCL-2 Positive Peripheral T Cell Lymphoma

Inclusion criteria:

* Histologically documented diagnosis of BCL-2 positive PTCL-NOS, AITL, TFH as defined in the 2016 edition of the World Health Organization (WHO) classification. Only patients with percentage of BCL-2 positive tu-mor cells ≥ 25% in the relapse biopsy, if available, or otherwise in the ini-tial biopsy, will be included onto the study;
* Age ≥ 18 years
* Relapsed or refractory to at least one previous standard line of treatment
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2
* At least one site of measurable nodal or extranodal disease at baseline ≥ 2.0 cm in the longest transverse diameter as determined by CT scan (MRI is allowed only if CT scan cannot be performed). Note: Patients with only bone marrow involvement are eligible
* Adequate hematological counts defined as follows:
* Absolute Neutrophil count (ANC) \> 1.0 x 10\^9/L unless due to bone marrow involvement by lymphoma
* Platelet count ≥ 50.000/mm\^3 unless due to bone marrow involvement by lymphoma
* Adequate renal function defined as follows:
* Creatinine clearance ≥ 30 mL/min
* Adequate hepatic function per local laboratory reference range as follows:
* Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x ULN
* Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syn-drome or of non-hepatic origin)
* Subject understands and voluntarily signs an informed consent form ap-proved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific pro-cedures
* Subject must be able to adhere to the study visit schedule and other pro-tocol requirements
* Subject must be able to swallow capsules or tablets
* Life expectancy ≥ 3 months
* Women must be:
* postmenopausal for at least 1 year (must not have had a natural menses for at least 12 months)
* surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy),
* completely abstinent (periodic abstinence from intercourse is not per-mitted) or if sexually active, be practicing a highly effective method of birth control (e.g., prescription oral contraceptives, contraceptive injec-tions, contraceptive patch, intrauterine device, double barrier method (e.g.: condoms, diaphragm, or cervical cap, with spermicidal foam, cream, or gel, male partner sterilization) as local regulations permit, be-fore entry, and must agree to continue to use the same method of con-traception throughout the study. They must also be prepared to contin-ue birth control measures for at least 1 month after terminating treat-ment.
* women of childbearing potential must have a negative pregnancy test at screening
* Men must agree to use an acceptable method of contraception (fort themselves or female partners as listed above) for the duration of the study. Men must agree to use a double barrier method of birth control and to not donate sperm during the study and for 1 month after receiving the last dose of study drug.

Male even if surgically sterilized (i.e., status postvasectomy) must agree to 1 of the following:

* practice effective barrier contraception during the entire study treatment period and through 1 months after the last dose of study drug, or
* agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods for the female part-ner\] and withdrawal are not acceptable methods of contraception)

Exclusion criteria

* Histological diagnosis different from BCL-2 positive PTCL-NOS, AITL, and TFH
* Allogeneic or autologous stem cell transplant within 6 months prior to the informed consent signature
* Treatment with any of the following within 7 days prior to the first dose of study drug:
* steroid therapy for anti-neoplastic intent
* moderate or strong cytochrome P450 3A (CYP3A) inhibitors (see Ap-pendix C for examples)
* moderate or strong CYP3A inducers (see Appendix C for examples)
* Subject has received any anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, investigational therapy, including targeted small molecule agents within 14 days prior to the first dose of study drug
* History of CNS involvement by lymphoma
* Administration or consumption of any of the following within 3 days prior to the first dose of study drug:
* grapefruit or grapefruit products
* Seville oranges (including marmalade containing Seville oranges)
* star fruit
* Previous treatment with a BCL-2 family protein inhibitor
* Subject is known to be positive for HIV (HIV testing is not required)
* Cardiovascular disease (NYHA class ≥2)
* Creatinine Clearance \< 30 mL/min
* Significant history of neurologic, psychiatric, endocrinologic, metabolic, immunologic, or hepatic disease that would preclude participation in the study or compromise ability to give informed consent.
* Any history of other active malignancies within 3 years prior to study en-try, with the exception of adequately treated in situ carcinoma of the cer-vix uterine, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin, previous malignancy confined and surgically re-sected with curative intent.
* Subject who has malabsorption syndrome or other condition which pre-cludes enteral route of administration.
* Evidence of other clinically significant uncontrolled condition(s) including, but not limited to uncontrolled and/or active systemic infection (viral, bac-terial or fungal)
* Active HBV positive hepatitis
* The following categories of patients HBV positive but with non evidence of active hepatitis may be considered for the study:
* HBsAg positive with HBV DNA \< 2000 UI/ml (inactive carriers); HBV DNA \> 2000 UI/ml is criteria of exclusion
* HBsAg negative but HBsAb positive
* HBsAg negative but HBcAb positive
* Patients HBsAg positive with HBV DNA \< 2000 UI/ml and HBsAg nega-tive but HBcAb positive will be eligible for the study only if they accept to receive prophylactic Lamivudine 100 mg/daily for all the period of treatment and at least for 12 months after the end of therapy. Treatment with ABT-199 should be stopped in case of hepatitis reactivation.
* Active HCV positive hepatitis
* If female, the patient is pregnant or breast-feeding.