Efficacy and Safety of Romidepsin CHOP vs CHOP in Patients With Untreated Peripheral T-Cell Lymphoma

Phase 3 Multi-center Randomized Study to Compare Efficacy and Safety of Romidepsin CHOP (Ro-CHOP) Versus CHOP in Patients With Previously Untreated Peripheral T-cell Lymphoma

Primary objective of the study is to compare the efficacy of romidepsin when administered with CHOP versus CHOP alone in subjects with previously untreated peripheral T-cell lymphoma (PTCL) in terms of progression-free survival (PFS) assessed according to Response criteria for malignant lymphoma 1999 by a Response Adjudication Committee (RAC).

This is a randomized multi-center phase III study, to compare efficacy and safety of Ro-CHOP with standard CHOP regimen in patients with previously untreated, histologically proven PTCL. Given the nature of the experimental agent, this study is an open-label study. Patients are randomized 1:1 to receive either (Arm A) cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) administered in 3 week cycles for 6 cycles [22] or (Arm B) romidepsin CHOP (Ro-CHOP) administered in 3 week cycles for 6 cycles. In the Ro-CHOP arm, romidepsin will be administered at a dose of 12 mg/m² IV on day 1 and day 8 every 3 weeks. In this study, patients will advance through three phases of the study: screening phase, treatment phase and follow-up phase. Patients will receive study drug(s) for up to 6 cycles, or until unacceptable toxicity will develop or progression or voluntary withdrawal. Patients will be followed for survival until the earliest of either 80% of patients have died or 3 years from the last patient randomized. Three years after the primary analysis an update of the database will be done and a rerun of the analysis will be performed.

Inclusion Criteria:

1. Males and females of 18 years of age to 80 years of age.

2. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted.

3. Able to adhere to the study visit schedule and other protocol requirements.

4. Patients with histologically proven peripheral T-cell lymphoma (PTCL), not previously treated; the following subtypes as defined by the World Health Organization (WHO) classification (2008;2011) may be included, whatever the Ann Arbor stage (I - IV):

   a. Nodal types: i. PTCL, not otherwise specified ii. Angioimmunoblastic T-cell lymphoma iii. Anaplastic large cell lymphoma, anaplastic lymphoma kinase (ALK)-negative type

   b. Extra-nodal types: i. Enteropathy-associated T-cell lymphoma ii. Hepato-splenic T-cell lymphoma iii. Subcutaneous panniculitis-like T-cell lymphoma iv. Primary cutaneous gamma-delta T-cell lymphoma v. Primary cutaneous cluster of differentiation 8 positive (CD8+) aggressive epidermotropic lymphoma vi. Primary cutaneous cluster of differentiation 4 positive (CD4+) small/medium T-cell lymphoma

   c. Other non classifiable peripheral T-cell lymphoma

5. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2

6. Negative pregnancy test for Females of ChildBearing Potential (FCBP)

7. Female patients of child bearing potential must use an effective method of birth control (i.e. hormonal contraceptive, intrauterine device, diaphragm with spermicide, condom with spermicide or abstinence) during treatment period and 1 month thereafter; Males must use an effective method of birth control during treatment period and 3 months thereafter.

8. Life expectancy of ≥ 90 days (3 months).

Exclusion Criteria:

1. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from participating in the study.

2. Any condition that confounds the ability to interpret data from the study.

3. Other types of lymphomas, e.g. B-cell lymphoma

4. The following types of T cell lymphomas:

   1. Adult T-cell lymphoma/leukemia (HTLV-1 related T-cell lymphoma)
   2. Extranodal T-cell/Natural Killer (NK)-cell lymphoma, nasal type
   3. Anaplastic large cell lymphoma, ALK-positive type
   4. Cutaneous T cell lymphoma (mycosis fungoid, Sézary syndrome)
   5. Primary cutaneous cluster of differentiation antigen 30 positive (CD30+) T-cell lymphoproliferative disorder
   6. Primary cutaneous anaplastic T-cell lymphoma

5. Previous treatment for PTCL with immunotherapy or chemotherapy except for short-term corticosteroids (duration of ≤ 8 days) before randomization

6. Previous radiotherapy for PTCL except if localized to one lymph node area

7. Patients planned for autologous or allogeneic transplant as consolidation in first line

8. Central nervous system -meningeal involvement

9. Contraindication to any drug contained in the chemotherapy regimen,

10. Subjects with HIV positivity

11. Subjects with active hepatitis B or C. Chronic carriers of Hepatitis B virus (HBV) without HBV DNA positive blood are eligible. Subjects with non-active hepatitis C (with normal transaminases) are eligible.

12. Any of the following laboratory abnormalities, except if secondary to the lymphoma:

    1. Absolute neutrophil count (ANC) < 1,500 cells/mm3 (1.5 x 109/L),
    2. Platelet count < 100,000/mm3 (100 x 109/L), or < 75,000/mm3 if bone marrow is involved,
    3. Serum Aspartate Aminotransferase (ASAT/AST) or Alanine Aminotransferase (ALAT/ALT) ≥ 3.0 x Upper Limit of Normal (ULN),
    4. Serum total bilirubin > 2 x ULN, except in case of hemolytic anemia,
    5. K+ and Mg2+ levels < Lower Limit of Normal (LLN), except if corrected per protocol guidance before beginning the romidepsin infusion

13. Serum creatinine > 2.0 x ULN

14. Prior history of malignancies other than lymphoma (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast or untreated prostatic cancer without any plan for a treatment) unless the patient has been free of the disease for ≥ 3 years

15. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing the informed consent form

16. Any known cardiac abnormalities such as:

    1. Patients with congenital long QT syndrome
    2. Corrected QT interval > 480 msec (using the Fridericia formula)
    3. Myocardial infarction within 6 months of cycle 1 day 1
    4. History of or concomitant significant cardiovascular disease
    5. Ejection fraction <45% by multigated acquisition (MUGA) scan or by echocardiogram;

17. Concomitant use of drugs that may cause a significant prolongation of the corrected QT interval (QTc)

18. Patients who have received more than 200 mg/m2 doxorubicin

19. Concomitant use of strong CYP3A4 inhibitors

20. Concomitant use of therapeutic warfarin due to a potential drug interaction. Use of a low dose of warfarin or another anticoagulant to maintain patency of venous access port and cannulas is permitted.

21. Clinically significant active infection

22. Use of any standard or experimental anti-cancer drug therapy within 28 days of the initiation (Day 1) of study drug

23. Pregnant or lactating females or women of childbearing potential not willing to use an adequate method of birth control for the duration of the study.