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

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ClinicalTrials.gov Identifier: NCT04639843
Recruitment Status : Not yet recruiting
First Posted : November 23, 2020
Last Update Posted : February 25, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

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....


Condition or disease Intervention/treatment Phase
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 Drug: CC-486 (5-azacitidine) Drug: Duvelisib Drug: Romidepsin Drug: Doxorubicin Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study of Doxorubicin, CC-486 (5-azacitidine), Romidepsin, and Duvelisib (hARD) for T-cell Lymphoma
Estimated Study Start Date : March 2, 2021
Estimated Primary Completion Date : October 31, 2023
Estimated Study Completion Date : December 31, 2023


Arm Intervention/treatment
Experimental: 1- Experimental Treatment: Dose Escalation
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)
CC-486 (5-azacitidine) with a dose of 300mg oral intake daily will be given on day 1 to day 10 for 8 cycles.

Drug: Duvelisib
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).

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

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

Experimental: 2 - Experimental Treatment: Dose Expansion
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)
CC-486 (5-azacitidine) with a dose of 300mg oral intake daily will be given on day 1 to day 10 for 8 cycles.

Drug: Duvelisib
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).

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

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




Primary Outcome Measures :
  1. Safety and tolerability [ Time Frame: 8 cycles ]
    Rate and severity of AEs will be summarized by grade and type of toxicity

  2. Maximum tolerated dose (MTD) [ Time Frame: 21 days ]
    Frequency (number and percentage) of treatment emergent adverse events


Secondary Outcome Measures :
  1. Progression-free survival [ Time Frame: every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually ]
    The response rate will be determined and reported along with a 95% confidence interval

  2. Overall Repsonse Rate [ Time Frame: 8 cycles ]
    The response rate will be determined and reported along with a 95% confidence interval

  3. Complete Response Rate [ Time Frame: 8 cycles ]
    The response rate will be determined and reported along with a 95% confidence interval

  4. Duration of response (DOR) [ Time Frame: every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually ]
    The response rate will be determined and reported along with a 95% confidence interval

  5. Overall Survival (OS) [ Time Frame: every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually ]
    The response rate will be determined and reported along with a 95% confidence interval

  6. Event Free Survival (EFS) [ Time Frame: every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually ]
    The response rate will be determined and reported along with a 95% confidence interval



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

-INCLUSION CRITERIA:

  1. 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
  2. PTCL from initial diagnosis or recurrence must be histologically or cytologically proven and diagnosis be confirmed by the Laboratory of Pathology, NCI.
  3. 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 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).
  4. Disease must be measurable with at least one measurable lesion by RECIL 2017 criteria or with an abnormal clonal T-cell population detectable by peripheral blood flow cytometry.
  5. Age >=18 years

    NOTE: Because no dosing or adverse event data are currently available on the use of duvelisib combination with romidepsin and CC-486 (5-azacitidine) in patients <18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.

  6. ECOG performance status <=2.
  7. LVEF within institutional parameters as determined by echocardiography.
  8. DLCO/VA Adjusted and FEV1 >=50% of reference.
  9. Adequate organ and marrow function as defined below:

    Absolute neutrophil count >= 1,000/mcL

    Platelets >= 75,000/mcL

    Total bilirubin <= 1.5 X institutional upper limit of normal (ULN)

    AST(SGOT)/ALT(SGPT) <= 2.5 X institutional ULN

    Creatinine clearance >= 60 mL/min/1.73 m^2 calculated by calculated using eGRF in the clinical lab

  10. For women of childbearing potential (WCBP): negative serum <= human chorionic gonadotropin ( <=hCG) pregnancy test during screening. A negative pregnancy test is also required within 7 days before first treatment; screening results may be used for treatment if they fall within the required window.

    NOTE: WCBP is defined as sexually mature woman who has not undergone surgical sterilization or who has not been naturally postmenopausal for at least 12 consecutive months for women >55 years of age)

  11. Male and female participants of reproductive potential (i.e., not surgically sterile or female subjects who are not postmenopausal), must be willing to use a highly effective method of contraception for the duration of the study treatment and 3 months after the last dose of duvelisib and/or romidepsin and for 6 months after the last dose of doxorubicin, whichever is longer.
  12. For patients that have received allogeneic HSCT, a minimum of 100 days must have elapsed before enrollment. Patients must have been off of immunosuppressive medications for prophylaxis of GVHD for at least four weeks before enrollment.
  13. Ability of subject to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

  1. Patients who are receiving any other investigational agents.
  2. Patients in need of immediate cytoreduction.
  3. 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.
  4. Prior lifetime doxorubicin therapy >= 400 mg/m^2.
  5. Prior radiation therapy to chest with fields involving the heart.
  6. Major surgery within 4 weeks prior to start of treatment
  7. History of tuberculosis treatment within the 2 years prior to start of treatment
  8. Administration of a live or live attenuated vaccine within 6 weeks prior to start of treatment
  9. 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.
  10. 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.
  11. Systemic treatment for acute or chronic graft versus host disease (GVHD) within 12 weeks of the first dose of duvelisib
  12. Cohort 1 (Dose Escalation) only: history of grade 3/4 GVHD
  13. Patients with active acute or chronic GVHD
  14. 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.
  15. Prior history of drug-induced colitis or drug-induced pneumonitis.
  16. History of chronic liver disease or veno-occlusive disease
  17. History of allergic reactions or known or suspected hypersensitivity attributed to compounds of similar chemical or biologic composition to duvelisib, romidepsin and CC-486 (5-azacitidine).
  18. Ongoing treatment with systemic steroids at a dose higher than 20 mg of prednisone (or equivalent) once daily
  19. Patients with uncontrolled intercurrent illness including, but not limited to, detectable CMV or EBV viral load, and ongoing or active bacterial, fungal, or viral infection requiring systemic therapy, with the following exceptions:

    • Human immunodeficiency virus (HIV)-infected patients on effective anti- retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
    • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable and on suppressive therapy, if indicated.
    • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
    • Subjects on antimicrobial, antifungal, or antiviral prophylaxis.
  20. History of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), celiac disease (i.e., sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism or excretion of the study drugs and/or predispose the subject to an increased risk of gastrointestinal toxicity.
  21. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association Classification Class II), congenital long QT syndrome, or other serious cardiac arrhythmia including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min).
  22. Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or other causes.
  23. Uncontrolled hypertension, i.e., blood pressure (BP) of >=160/95 at screening; patients who have a history of hypertension controlled by medication must be on a stable dose (for at least one month) and meet all other inclusion criteria.
  24. Triplicate average baseline QTcF interval >= 480 ms during screening
  25. Patients taking drugs leading to significant QT prolongation Note: A 5 half-life washout period must have elapsed following the use of these drugs prior to administration of romidepsin.
  26. Concomitant use of rifampin and other strong CYP3A4 inhibitors and inducers within 2 weeks prior to start of treatment.
  27. Inability to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), or herpes zoster (VZV).
  28. Other severe acute or chronic medical conditions including psychiatric conditions such as recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
  29. Pregnant or lactating women. NOTE: Pregnant women are excluded from this study because based on findings in animals and its mechanism of action, duvelisib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of duvelisib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal mortality. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with duvelisib, breastfeeding should be discontinued if the mother is treated with duvelisib. These potential risks may also apply to other agents used in this study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04639843


Contacts
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Contact: NCI Medical Oncology Referral Office (240) 760-6050 ncimo_referrals@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Milos Miljkovic, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04639843    
Other Study ID Numbers: 200169
20-C-0169
First Posted: November 23, 2020    Key Record Dates
Last Update Posted: February 25, 2021
Last Verified: November 19, 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
TCL
Histone Deacetylase Inhibitors (HDACi)
Kinase Inhibitors
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, T-Cell
Leukemia, T-Cell
Leukemia-Lymphoma, Adult T-Cell
Lymphoma, Extranodal NK-T-Cell
Enteropathy-Associated T-Cell Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Leukemia
Doxorubicin
Romidepsin
Azacitidine
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites