Doxorubicin, CC-(486) (5-azacitidine), Romidepsin, and Duvelisib (hARD) for T-cell Lymphoma

NCT04639843 | Withdrawn Phase 1 FDA Drug

• 2 other identifiers: 20016920-C-0169
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Background: T-cell lymphomas (TCLs) are rare cancers. Many types of TCLs do not develop in the lymph nodes but in places like the skin, spleen, and bone marrow. Researchers want to see if a mix of 4 drugs can help people with TCL. Objective: To test if the combination of romidepsin, CC-486 (5-azacitidine), duvelisib, and doxorubicin can be used safely in people with TCL. Eligibility: Adults 18 and older with TCL that is newly diagnosed or that returned after or did not respond to standard treatments. Design: Participants will be screened on a separate protocol. They may have a tumor biopsy. Participants will have medical histories, medicine reviews, and physical exams. Their ability to do daily activities will be assessed. They will have blood and urine tests. Participants will take duvelisib and CC-486 (5-azacitidine) by mouth. They will get romidepsin and doxorubicin by intravenous infusion. They will take the drugs for up to eight 21-day cycles. They will keep a medicine diary. Participants will have a bone marrow aspiration and/or biopsy. Bone marrow will be taken through a needle inserted in the hip. Participants will have tumor imaging scans. Some may have a brain MRI and lumbar puncture. Some may have skin assessments. Participants will give blood, saliva, and tumor samples for research. Participants will have a safety visit 30 days after treatment ends. Then they will have follow-up visits every 60 days for 6 months, then every 90 days for 2 years, and then every 6 months for 2 years. Then they will have yearly visits until their disease gets worse or they start a new treatment....

Conditions

Adult T-cell Leukemia/Lymphoma; Extranodal NK-/T-cell Lymphoma, Nasal Type; Enteropathy-Associated T-Cell Lymphoma; Monomorphic Epiteliotrophic Intestinal T-cell Lymphoma; Hepatosplenic T-cell Lymphoma

Keywords

TCL; Histone Deacetylase Inhibitors (HDACi); Kinase Inhibitors

Outcome Measures

Primary Outcomes (2)

• Safety and tolerability

  Rate and severity of AEs will be summarized by grade and type of toxicity

  8 cycles

• Maximum tolerated dose (MTD)

  Frequency (number and percentage) of treatment emergent adverse events

  21 days

Secondary Outcomes (6)

• Progression-free survival

  every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually

• Overall Repsonse Rate

  8 cycles

• Complete Response Rate

  8 cycles

• Duration of response (DOR)

  every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually

• Overall Survival (OS)

  every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually

Study Arms (2)

1- Experimental Treatment: Dose Escalation

EXPERIMENTAL

Duvelisib (PO BID) at escalating doses of 25, 50 and 75 mg/BID on days -14 to 14 of C1 and days 1-14 of all other cycles of each 21- day cycle (max 8 cycles) with CC-486 (5-azacitidine) (PO) at 300mg/day on days 1-10, romidepsin at 12mg/m2 (IV) on Days 1 and 8 of each cycle and doxorubicin (IV) at 25 mg/ m2 on Day 1 of cycles 3-8 (Cycles 3-6 for patients with prior anthracycline-based therapy), to determine RP2D of duvelisib and doxorubicin

Drug: CC-486 (5-azacitidine); Drug: Duvelisib; Drug: Romidepsin; Drug: Doxorubicin

2 - Experimental Treatment: Dose Expansion

EXPERIMENTAL

Duvelisib (PO BID) at RP2D on days -14 to 14 of C1 and days 1-14 of all other 21-day cycle (max 8 cycles) with CC-486 (5-azacitidine) at 300mg/day (PO) on days 1-10, romidepsin at 12mg/m2 (IV) on days 1 and 8 of each cycle, and doxorubicin at 25 mg/m2 on day 1 of Cycles 3-8 (Cycles 3-6 for patients with prior anthracycline-based therapy

Drug: CC-486 (5-azacitidine); Drug: Duvelisib; Drug: Romidepsin; Drug: Doxorubicin

Interventions

CC-486 (5-azacitidine) DRUG

CC-486 (5-azacitidine) with a dose of 300mg oral intake daily will be given on day 1 to day 10 for 8 cycles.

1- Experimental Treatment: Dose Escalation; 2 - Experimental Treatment: Dose Expansion

Duvelisib DRUG

Duvelisib by oral intake at escalating doses of 25, 50 and 75 mg/BID on days -14 to 14 of the 1st cycle then days 1-14 of Cycles 2-8 of each 21- day cycle (max 8 cycles).

1- Experimental Treatment: Dose Escalation; 2 - Experimental Treatment: Dose Expansion

Romidepsin DRUG

Romidepsin (12mg/m2) will be administered on days 1 and 8 of each cycle through a peripheral or central intravenous catheter for 8 cycles.

1- Experimental Treatment: Dose Escalation; 2 - Experimental Treatment: Dose Expansion

Doxorubicin DRUG

Doxorubicin at 25 mg/ m2 by IV infusion on Day 1 of cycles 3-8.

1- Experimental Treatment: Dose Escalation; 2 - Experimental Treatment: Dose Expansion

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with newly diagnosed (Cohort 2) or relapsed/refractory (Cohorts 1 and 3) T-cell lymphoma (TCL) defined as follows (per 2016 WHO classification):
• Adult T-cell leukemia/lymphoma
• Extranodal NK-/T-cell lymphoma, nasal type
• Enteropathy-associated T-cell lymphoma
• Monomorphic epiteliotrophic intestinal T-cell lymphoma
• Hepatosplenic T-cell lymphoma
• Subcutaneous panniculitis-like T-cell lymphoma
• Peripheral T-cell lymphoma, NOS
• Angioimmunoblastic T-cell lymphoma
• Follicular T-cell lymphoma
• Nodal peripheral T-cell lymphoma with TFH phenotype
• Anaplastic large-cell lymphoma, ALK+ and ALK- (only if relapsed/refractory after at least one line of systemic therapy, which must include brentuximab vedotin)
• Breast implant-associated anaplastic large-cell lymphoma Note: For relapsed patients, prior treatment may include allogeneic stem cell transplantation
• PTCL from initial diagnosis or recurrence must be histologically or cytologically proven and diagnosis be confirmed by the Laboratory of Pathology, NCI.
• For patients without circulating lymphoma cells detectable by flow cytometry, a formalin fixed tissue block or 15 slides of tumor sample (archival or fresh) must be available at enrollment for performance of correlative studies. NOTE: Patients without circulating malignant cells must be willing to have a tumor biopsy if prior tissue or adequate archival tissue is not available (i.e., post-enrollment and prior to treatment).

You may not qualify if:

• Patients who are receiving any other investigational agents.
• Patients in need of immediate cytoreduction.
• Chemotherapy or monoclonal antibody therapy within 4 weeks prior to start of treatment (6 weeks for nitrosoureas or mitomycin C); small molecule or radiation therapy within 2 weeks.
• Prior lifetime doxorubicin therapy \>= 400 mg/m\^2.
• Prior radiation therapy to chest with fields involving the heart.
• Major surgery within 4 weeks prior to start of treatment
• History of tuberculosis treatment within the 2 years prior to start of treatment
• Administration of a live or live attenuated vaccine within 6 weeks prior to start of treatment, or of mRNA and adenovirus-based vaccines within 2 weeks prior to start of treatment
• Patients who have received all of the planned study drugs - i.e., duvelisib, romidepsin, and CC-486 (5-azacitidine) - at any time point during prior treatments for TCL. Patients who have received one or two of the three drugs (alone or in combination) remain eligible.
• Patients with previous malignant disease other than the target malignancy within the last 5 years with the exception of basal or squamous cell carcinoma of the skin or cervical carcinoma in situ.
• Systemic treatment for acute or chronic graft versus host disease (GVHD) within 12 weeks of the first dose of duvelisib
• Cohort 1 (Dose Escalation) only: history of grade 3/4 GVHD
• Patients with active acute or chronic GVHD
• History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function. Pulmonary function testing (PFTs) will be evaluated at screening.
• Prior history of drug-induced colitis or drug-induced pneumonitis.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Lymphoma, Extranodal NK-T-Cell; Enteropathy-Associated T-Cell Lymphoma

Interventions

cc-486; duvelisib; romidepsin; Doxorubicin

Condition Hierarchy (Ancestors)

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, T-Cell; Lymphoma, Non-Hodgkin; Lymphoma

Intervention Hierarchy (Ancestors)

Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Study Officials

• Kevin C Conlon, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 20, 2020
• First Posted: November 23, 2020
• Study Start: November 3, 2022
• Primary Completion: November 3, 2022
• Study Completion: November 3, 2022
• Last Updated: November 4, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data will be available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.

Locations

US (1)