A Study of DR-01 in Subjects With Large Granular Lymphocytic Leukemia or Cytotoxic Lymphomas

Dren Bio

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Cutaneous PTCL-NOS (CD8+ or CD56+ and Cytotoxic Marker); LGLL - Large Granular Lymphocytic Leukemia; Cytotoxic PTCL-NOS (CD8+ or CD56+ and Cytotoxic Marker); Aggressive NK Cell Leukemia; Hydroa Vacciniforme-Like Lymphoproliferative Disorder; Subcutaneous Panniculitis-Like T-Cell Lymphoma; Extranodal NK/T Cell Lymphoma, Nasal Type; Primary Cutaneous Gamma-Delta T-Cell Lymphoma; Primary Cutaneous CD8+ Aggressive Epidermotropic T-Cell Lymphoma; Hepatosplenic T-cell Lymphoma; Enteropathy-Associated T-Cell Lymphoma; Systemic EBV1 T-cell Lymphoma, if CD8 Positive; Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma

Treatments: Drug: DR-01

Study type: Interventional

Funder types: Industry

Identifiers

NCT05475925

DR-01-ONC-001

Details and patient eligibility

About

This is a multicenter, first-in-human, Phase 1/2 study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and anti-tumor activity of DR-01 in adult patients with large granular lymphocytic leukemia or cytotoxic lymphomas

Enrollment: 200 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria (All Subjects):

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. Sufficient key organ performance and coagulation.

4. 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 from enrollment through at least 12 months after last dose of DR-01.

5. Male subjects must agree to use acceptable effective method(s) of contraception.

   Subjects with LGLL must also meet inclusion criteria 6 and 7.

6. Must have discontinued at least one prior line of systemic therapy.

7. Additional immunophenotypic and symptomatic criteria must be met.

   Disease-specific Inclusion Criteria (Cytotoxic Lymphomas):

   Subjects with cytotoxic lymphomas must also meet inclusion criteria 8,9, and 10.

8. Subjects must have failed at least one prior systemic regimens.

9. Availability of post-progression tissue sample or willingness to consent to a baseline biopsy.

10. Histologically confirmed diagnosis of a cytotoxic lymphoma by a hematopathologist (according to the WHO 2016 classification [Swerdlow 2016]).

11. For Part A only, evaluable disease is acceptable.

12. For Part B2 only, evaluable by the following response criteria as documented during Screening:

    1. For cytotoxic PTCL-NOS, ENKTL, MEITL, EATL, SPTCL - Subjects must have radiographically measurable disease by computed tomography (CT) or CT/positron emission tomography (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).
    2. For PCGDTCL, ET-CTCL, HVLPD, cytotoxic CuPTCL-NOS - Subjects with primary cutaneous variants must have at least 1 measurable lesion that is evaluable using the Olsen criteria (Olsen 2021) or have leukemic involvement that can be evaluated using modified TPLL response criteria (Staber 2019).
    3. For HSTCL, ANKL, SysEBV TCL - Subjects with hepatosplenic disease without measurable disease by Lugano criteria (Cheson 2014) or leukemic involvement in BM or peripheral blood that is evaluable for response using a modified TPLL response criteria (Staber 2019).

Exclusion Criteria:

Disease-specific Exclusion Criteria; LGLL and ANKL:

1. A reactive LGL lymphocytosis to a viral infection or LGL associated with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).

   The following exclusion criteria apply to all subjects:

2. Active systemic infection or severe localized infection requiring systemic antibiotics, antivirals or antifungals.

3. Active or suspected malignant central nervous system involvement.

4. Life-threatening, severe complications of malignancy (e.g., uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation).

5. Active known second malignancy.

6. Infection with human immunodeficiency virus (HIV) type 1 or 2 (HIV-1 or HIV-2).

7. 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.

8. History of clinically significant cardiac disease or congestive heart failure greater than New York Heart Association (NYHA) Class II.

9. 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 non-biological immunosuppressive drugs within 15 days or 5 half-lives (whichever is less) prior to C1D1.

10. Any condition requiring hormonal therapy (except for contraception, hormone replacement therapy and hormonal prophylaxis for a prior malignancy).

11. 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.

12. 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).

13. Autologous HSCT within 40 days of C1D1, allogeneic HSCT within 90 days

14. Any immunosuppressive therapy for GVHD for subjects who are post allogeneic HSCT.

15. Major surgery within 28 days of C1D1 (requires more than local anesthesia or plexus blockade).

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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200 participants in 7 patient groups

Part A Dose Escalation 1 mg/kg of DR-01

Experimental group

Description:

Subjects in this arm will initially receive 1 mg/kg at either the Primary regimen (bi-weekly dosing for fist month), Secondary regimen (doses at Days 1, 8, 15, 29 during first month), or Tertiary regimen (dosing days 1-5, 15, 29 during first month), followed by monthly dosing (up to 6 mg/kg) thereafter for up to 25 cycles total.

Treatment:

Drug: DR-01

Part A Dose Escalation 3 mg/kg of DR-01

Experimental group

Description:

Subjects in this arm will initially receive 3 mg/kg at either the Primary regimen (bi-weekly dosing for fist month), Secondary regimen (doses at Days 1, 8, 15, 29 during first month), or Tertiary regimen (dosing days 1-5, 15, 29 during first month), followed by monthly dosing (up to 10 mg/kg) thereafter for up to 25 cycles total.

Treatment:

Drug: DR-01

Part A Dose Escalation 6 mg/kg of DR-01

Experimental group

Description:

Subjects in this arm will initially receive 6 mg/kg at either the Primary regimen (bi-weekly dosing for fist month), Secondary regimen (doses at Days 1, 8, 15, 29 during first month), or Tertiary regimen (dosing days 1-5, 15, 29 during first month), followed by monthly dosing (up to 10 mg/kg) thereafter for up to 25 cycles total.

Treatment:

Drug: DR-01

Part A Dose Escalation 10 mg/kg of DR-01

Experimental group

Description:

Subjects in this arm will initially receive 10 mg/kg at either the Primary regimen (bi-weekly dosing for fist month), Secondary regimen (doses at Days 1, 8, 15, 29 during first month), or Tertiary regimen (dosing days 1-5, 15, 29 during first month), followed by monthly dosing (up to 10 mg/kg) thereafter for up to 25 cycles total.

Treatment:

Drug: DR-01

Part A Dose De-escalation 0.3 to <1 mg/kg of DR-01

Experimental group

Description:

This cohort would only be triggered should a DLT occur at Dose Level 1 or if recommended by the Safety Review Committee. Subjects in this arm would initially receive 0.3 to \<1 mg/kg at either the Primary regimen (bi-weekly dosing for fist month), Secondary regimen (doses at Days 1, 8, 15, 29 during first month), or Tertiary regimen (dosing days 1-5, 15, 29 during first month), followed by monthly dosing (up to 3 mg/kg) thereafter for up to 25 cycles total.

Treatment:

Drug: DR-01

Part B Dose Expansion (Cohort B1) Optimized Dose/Regimen of DR-01

Experimental group

Description:

Subjects in this arm will receive the pharmacologically optimized dose/regimen for LGL leukemia subjects determined in Part A. Depending on the selected dose/regimen, subjects will receive target dose at either the Primary regimen (bi-weekly dosing for fist month), Secondary regimen (doses at Days 1, 8, 15, 29 during first month), or Tertiary regimen (dosing days 1-5, 15, 29 during first month), followed by monthly dosing thereafter for up to 25 doses total.

Treatment:

Drug: DR-01

Part B Dose Expansion (Cohort B2) Optimized Dose/Regimen of DR-01

Experimental group

Description:

Subjects in this arm will receive the pharmacologically optimized dose/regimen for cytotoxic lymphoma subjects determined in Part A. Depending on the selected dose/regimen, subjects will receive target dose at either the Primary regimen (bi-weekly dosing for fist month), Secondary regimen (doses at Days 1, 8, 15, 29 during first month), or Tertiary regimen (dosing days 1-5, 15, 29 during first month), followed by monthly dosing thereafter for up to 25 doses total.

Treatment:

Drug: DR-01