DR-01-ONC-001 (DREN BIO)

Description

This is a multicenter, open-label, Phase 1/2, dose escalation, dose extension, and cohort expansion study to evaluate the safety and efficacy of DR-01 for the treatment of adult subjects with LGLL or cytotoxic lymphomas.

Objectifs principaux

Primary:
• To evaluate the safety and tolerability of escalating doses of DR-01 in adult subjects with relapsed/refractory LGLL or cytotoxic lymphomas

• To determine potential pharmacologically optimized dose/regimen(s) for DR-01 for the LGLL and cytotoxic lymphoma populations

Principaux critères d’éligibilité

1. ≥18 years of age.
2. Able to understand and comply with protocol-required study procedures and voluntarily sign a written informed consent document
3. Prothrombin time or international normalized ratio (INR) ≤1.5 × ULN
4. Activated partial thromboplastin time ≤1.5 × ULN
5. Creatinine clearance (CrCl) ≥50 mL/min (using Cockcroft-Gault
6. Total bilirubin ≤1.5 × ULN (≤3 × ULN if known Gilbert’s disease)
7. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN (≤5 × ULN if malignant involvement of the liver and approval by the medical monitor)                                                                                        8. Amylase <1.5 × ULN
9. Female subjects of childbearing potential (postmenarcheal, has an intact uterus and at least one ovary, and is <1 year postmenopausal) must agree to use a highly effective method of contraception (as specified in Appendix D or as permitted by regional regulatory authorities) from enrollment through at least 12 months after last dose of DR-01
10. Male subjects must agree to use acceptable effective method(s) of contraception (as specified in Appendix D or as permitted by regional regulatory authorities) from enrollment through at least 12 months after last dose of DR-01                                                                                                  16. ECOG performance status 0 – 1 (Oken 1982)
17. Subjects must have failed at least one prior systemic regimen and still require therapy. If concurrent radio-chemotherapy was applied, the chemotherapy part will be considered one line of systemic therapy
18. Availability of post-progression tissue sample or willingness to consent to a baseline biopsy
19. Histologically confirmed diagnosis of lymphoma by a hematopathologist (according to the WHO 2016 classification [Swerdlow 2016]). Eligible histologies are as follows:
a. Primary cutaneous gamma-delta T-cell lymphoma
b. Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma
c. Hepatosplenic T-cell lymphoma
d. Subcutaneous panniculitis-like T-cell lymphoma (almost always ab disease)
e. Aggressive NK-cell leukemia
f. Systemic Epstein-Barr virus (EBV)1 T-cell lymphoma, if CD8 positive
g. Hydroa vacciniforme-like lymphoproliferative disorder
h. Extranodal NK-/T-cell lymphoma, nasal type
i. Enteropathy-associated T-cell lymphoma
j. Monomorphic epitheliotropic intestinal T-cell lymphoma
k. Other atypical pathology findings that suggest lymphoma is likely to be cytotoxic (as defined by expression of CD8 or CD56, and at least 1 cytotoxic marker) with Medical Monitor approval
20. For Part A only, evaluable disease is acceptable
21. For Part B2 only, evaluable by one of the following response criteria as documented during Screening:
a. Subjects must have radiographically measurable disease by computed tomography (CT) or CT/positron emission tomography (CT/PET) scan defined as at least one node measuring >1.5 cm or measurable extranodal lesion of at least 1.0 cm in longest diameter to be evaluated by Lugano
criteria (Cheson 2014).
b. Subjects with primary cutaneous variants must have at least 1 measurable lesion that is evaluable
using the Olsen criteria (Olsen 2021) or leukemic involvement that can be evaluated using a
modified TPLL response criteria (Staber 2019).
c. Subjects with hepatosplenic disease or other variants that do not have measurable disease by Lugano criteria (Cheson 2014) may be eligible upon discussion with the Medical Monitor if they have identifiable leukemic involvement in BM or peripheral blood (meeting the CD8+ cytotoxic phenotype definition) that can be evaluated for response using a modified TPLL response criteria (Staber 2019), or skin involvement that can be evaluated using Olsen criteria (Olsen 2021).

Exclusion Criteria

3. <750/mm3 neutrophils
The following exclusion criteria apply to all subjects:
4. <50,000/mm3 thrombocytes (for HSTCL and ANKL where leukemia manifestation is common, a lower platelet count may be allowed with Medical Monitor approval)
5. Active systemic infection or severe localized infection requiring systemic antibiotics, antivirals or antifungals
6. Active or suspected malignant central nervous system involvement
7. Life-threatening, severe complications of malignancy (e.g., uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation)
8. Active known second malignancy with the exception of any of the following:
a. Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer
b. Adequately treated Stage I cancer from which the subject is currently in remission and has been in remission for at least 2 years without therapeutic intervention (anti-hormonal therapy is acceptable)
c. Low-risk prostate cancer with Gleason score <7 and prostate-specific antigen (PSA) <10 ng/mL
9. Infection with human immunodeficiency virus (HIV) type 1 or 2 (HIV-1 or HIV-2)
10. Hepatitis B infection (hepatitis B virus surface antigen [HBsAg] positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid). Subjects with HCV with undetectable virus after treatment are eligible.
11. History of clinically significant cardiac disease or congestive heart failure greater than New York Heart Association (NYHA) Class II. Major cardiac abnormalities and clotting abnormalities (e.g., uncontrolled angina, unstable arrhythmias, pulmonary embolism, deep venous thrombosis, cerebrovascular accident, myocardial infarction, pericardial effusion, restrictive cardiomyopathy, severe untreated valvular stenosis) within 6 months prior to C1D1, except for adequately treated catheter-related venous thrombosis occurring more than 1 month before C1D1
12. Hemophagocytic lymphohistiocytosis (HLH); subjects with signs and symptoms of HLH must have HLH ruled out by a BM biopsy
13. Electrocardiogram (ECG) QT interval corrected for heart rate (QTc) >475 msec, measured by Fridericia’s formula (QTcF = QT/[RR^0.33])          14. Use of biotin (i.e., vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 μg (NIH 2022). Note: subjects who switch from a high dose to a dose of ≤30 μg/day are eligible.
15. Use of systemic corticosteroids at prohibited dose levels within 15 days prior to C1D1 (except for prophylaxis for radiodiagnostic contrast reactions and study-defined premedication) or use of other nonbiological immunosuppressive drugs within 15 days or 5 half-lives (whichever is less) prior to C1D1
16. Any condition requiring hormonal therapy (except for contraception, hormone replacement therapy and hormonal prophylaxis for a prior malignancy)
17. Any other medical or psychiatric condition, or laboratory abnormality that would increase the risk associated with study participation, in the opinion of the Investigator or Medical Monitor
18. Non-biologics anticancer therapy (e.g., chemotherapy, irradiation) within 14 days or 5 half-lives (whichever is less) of C1D1
19. Use of biological therapies within 30 days of C1D1
20. Toxicities from previous anticancer therapies must have resolved to baseline levels or to Grade 1 (except for alopecia, peripheral neuropathy, or hematologic parameters meeting inclusion criteria)
21. Autologous hematopoietic stem cell transplantation (HSCT) within 40 days of C1D1, allogeneic HSCT within 90 days
22. Any immunosuppressive therapy for graft versus host disease (GVHD) for subjects who are post allogeneic HSCT
23. Major surgery within 28 days of C1D1 (requires more than local anesthesia or plexus blockade)