Phase II Study of Folotyn With Leucovorin to Prevent/Reduce Mucositis in Patients With Hematological Malignancies

This is a Phase 2, single-arm, open-label, multicenter study to determine the effect of leucovorin in preventing or reducing Folotyn-related Grade 2 or higher oral mucositis in patients with hematological malignancies including PTCL and CTCL.

Patients with hematological malignancies, including PTCL and CTCL, will be enrolled based on meeting all protocol eligibility criteria. The primary endpoint will be evaluated in the first 7-week treatment cycle. For patients who respond to study treatment, the Investigator can treat patients for a total of 6 cycles. Approximately 37 patients will be enrolled. Safety, as assessed by reported SAEs, will continue to be monitored during the optional treatment period. Efficacy will be followed to the extent that it is evaluated according to the Institution's standard of care. No formal analysis of efficacy will be made.

• Folotyn and Leucovorin (Drug), also known as Pralatrexate (Folotyn)
• Folic Acid (Drug): Folic acid (1.0 mg PO QD) is to be initiated at least 10 days prior to Folotyn administration, or per the USPI for Folotyn.
• Vitamin B12 (Drug): Vitamin B12 (1 mg IM) is to be administered within 10 weeks prior to initiation of Folotyn and can be administered during Screening. Subsequent vitamin B12 injections may be given the same day as treatment with Folotyn and patients are to receive vitamin B12 every 8 to 10 weeks while treated with Folotyn.

Primary outcomes

• Grade 2 Oral Mucositis Prevention [15 weeks]: To evaluate the effect of leucovorin in preventing or reducing Folotyn-related Grade 2 or higher oral mucositis.

Secondary outcomes

• Grade 3 Oral Mucositis Prevention [15 weeks]: To evaluate the effect of leucovorin in preventing or reducing Folotyn-related Grade 3 or higher oral mucositis.
• Grade 2 Oral Mucositis Duration of first occurrence [15 weeks]: To evaluate the time to first occurrence of Folotyn-related Grade 2 or higher oral mucositis.
• Grade 2 Oral Mucositis Duration [15 weeks]: To evaluate the duration of Folotyn-related Grade 2 or higher oral mucositis.
• Effectiveness of Leucovorin in Folotyn dose modification [15 weeks]: To evaluate the effect of leucovorin on the number and proportion of patients whose subsequent dose of Folotyn is omitted, delayed, or reduced due to the onset of oral mucositis.
• Objective Response Rate [17 weeks]: To evaluate objective response rate (ORR) of Folotyn in patients with relapsed or refractory (R/R) PTCL.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Patient is diagnosed with hematological malignancies including PTCL and CTCL and are eligible for treatment with a dose of 30 mg/m\^2
2. Patient is at least 18 years of age
3. Patient has been informed of the investigational nature of this study and has given written Informed Consent and is able to adhere to dosing and visit schedules and meet all study requirements
4. Patient has recovered from the toxic effects of prior therapy, and is at least 30 days from the most recent cytotoxic therapy, prior to enrollment
5. Patient has adequate hematologic, hepatic, and renal function as defined by:

   * ANC ≥1000/µL
   * Platelet count ≥100,000/µL
   * Total bilirubin ≤1.5 mg/dL
   * Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT), alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT), and gamma-glutamyltransferase (GGT) ≤2.5 xupper limit of normal (ULN) (AST/ALT/GGT ≤5 xULN if documented hepatic involvement with lymphoma)
   * Creatinine ≤2.0 mg/dL or calculated creatinine clearance ≥50 mL/min
6. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2
7. Females of childbearing potential are to agree to practice a medically acceptable contraceptive regimen (including a barrier method) from study treatment initiation until at least 30 days after the last administration of Folotyn or leucovorin, whichever is last, and are to have a negative urine beta human chorionic gonadotropin (β-HCG) pregnancy test within 14 days prior to the first day of study treatment. Females who are postmenopausal for at least 1 year (defined as >12 months since last menses) or are surgically sterilized do not require this test
8. Male patients are to agree to use a barrier method of contraception from study treatment initiation until at least 90 days after the last administration of Folotyn

Exclusion Criteria:

1. Patient has congestive heart failure Class III/IV according to the New York Heart Association (NYHA) Functional Classification
2. Patient has uncontrolled hypertension
3. Patient has known, uncontrolled human immunodeficiency virus (HIV)-positive diagnosis
4. Patient has symptomatic central nervous system (CNS) metastases or lesions for which treatment is required. Patients who received prophylactic CNS treatment are eligible
5. Patient has an active uncontrolled infection, underlying medical condition, or other serious illness that would impair the ability of the patient to receive protocol treatment
6. Patient has had major surgery within 14 days prior to enrollment
7. Patient has used any investigational drugs, biologics, or devices within 14 days prior to study treatment or plans to use any of these during the course of the study
8. Patient has had previous exposure to Folotyn within 6 months of study enrollment
9. Patient is pregnant or breast-feeding

• Results publication: Iyer SP, Dakhil S, Shinohara MM, Zain J, Acosta M, Foss F. Pralatrexate injection combined with oral leucovorin for mucositis management in PTCL/CTCL treatment: a multicenter phase 2 trial. Blood Neoplasia. 2024 Nov 2;2(1):100055. doi: 10.1016/j.bneo.2024.100055. eCollection 2025 Feb. PMID 40546726

• Wasim Khan, MD, Study director, Acrotech Biopharma Inc.