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Efficacy and Safety of Oral Azacitidine (CC-486) Compared to Investigator's Choice Therapy in Patients With Relapsed or Refractory Angioimmunoblastic T Cell Lymphoma

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ClinicalTrials.gov Identifier: NCT03703375
Recruitment Status : Not yet recruiting
First Posted : October 12, 2018
Last Update Posted : October 12, 2018
Sponsor:
Information provided by (Responsible Party):
Celgene

Brief Summary:

This study is a multicentric, open-label, randomized phase 3 trial. The study will be conducted in select countries in Europe and South Korea sponsored by LYSARC and in Japan sponsored by Celgene. There will be a combined enrollment target of 86 randomized patients, with approximately 14 randomized patients from Japan.

The enrollment to the randomized study will start at European sites in parallel to a safety run-in part in Japan. A safety run-in will be conducted to confirm the tolerability of oral azacitidine at doses of 100 mg and 200 mg QD in Asian patients. Once oral azacitidine at 200 mg QD is confirmed as tolerable, Asian patients from Japan and South Korea will start to be randomized into the main study. Additional patients (non-randomized) are anticipated to enroll to the safety run-in.


Condition or disease Intervention/treatment Phase
Lymphoma, T-Cell Drug: Azacitidine Drug: Romidepsin Drug: Gemcitabine Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 86 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized Phase 3 Study Evaluating the Efficacy and Safety of Oral Azacitidine (CC-486) Compared to Investigator's Choice Therapy in Patients With Relapsed or Refractory Angioimmunoblastic T Cell Lymphoma
Estimated Study Start Date : October 15, 2018
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021


Arm Intervention/treatment
Experimental: Administration of Oral Azacitidine (CC-486)
Oral azacytidine 300 mg during 14 first days of 28-days cycle for European (EU) patients, Oral azacytidine 200 mg during 14 first days of 28-days cycle for Asian patients (Treatment until progression, patient decision or toxicity)
Drug: Azacitidine
Azacitidine
Other Name: CC-486

Active Comparator: Investigator's choice therapy - Romidepsin
Romidepsin 14mg/m2 on days 1, 8 and 15 of a 28-days cycle (Treatment until progression, patient decision or toxicity)
Drug: Romidepsin
Romidepsin

Active Comparator: Investigator's choice therapy - Gemcitabine
Gemcitabine 1000mg/m2 on days 1, 8 and 15 of a 28-days cycle (during 6 cycles)
Drug: Gemcitabine
Gemcitabine




Primary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: 18 months after first randomization ]
    Is the time from randomization into the study to the first observation of documented disease progression or death due to any cause.

  2. Progression Free Survival (PFS) [ Time Frame: 35 months after first randomization ]
    Is the time from randomization into the study to the first observation of documented disease progression or death due to any cause.


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: 40 months after first randomization ]
    Is the time from the date of randomization to the date of death from any cause. Alive patients will be censored at their last contact.

  2. Progression Free Survival (PFS) by Independent Review Committee (IRC) [ Time Frame: 40 months after first randomization ]
    Is the time from randomization into the study to the first observation of documented disease progression or death due to any cause.

  3. Overall Response Rate (ORR) [ Time Frame: 40 months after first randomization ]
    Is the percentage of Complete Response (CR) + Partial Response (PR) among all patients.

  4. Complete Response Rate (CRR) [ Time Frame: 40 months after first randomization ]
    Is the percentage of Complete Response (CR) among all patients.

  5. Duration of Response [ Time Frame: 40 months after first randomization ]
    Is the time from attainment of CR or PR to the date of first documented disease progression, relapse (local assessment) or death from any cause.

  6. Time to Response [ Time Frame: 40 months after first randomization ]
    Is the time from randomization to the date of attainment of CR or PR until end of treatment.

  7. PFS2 using local assessment of progressive disease [ Time Frame: 40 months after first randomization ]
    Is the time from randomization to objective tumor progression on next-line treatment or death from any cause.

  8. EORTC QLQ-C30 [ Time Frame: 2 years after last randomization ]
    The QLQC30 is composed of both multi-item scales and single item measures. These include five functional scales (physical, role, emotional, cognitive and social), three symptom scales (fatigue, nausea/vomiting, and pain), a global health status/QOL scale, and six single items (dyspnoea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties).

  9. Adverse Events (AEs) [ Time Frame: 2 years after last randomization ]
    Number of subjects with Adverse Event



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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. Patient is ≥ 18 years of age at the time of signing the informed consent form (ICF).
  2. Patient must understand and voluntarily sign an ICF prior to any study-specific assessments/procedures being conducted.
  3. Patient is willing and able to adhere to the study visit schedule and other protocol requirements
  4. Patient had local diagnosed peripheral T cell lymphoma (PTCL) with T-follicular helper (TFH) phenotype according to the criteria of the latest WHO classification based on a surgical lymph node biopsy or needle core biopsy including any one of

    • Angioimmunoblastic T cell lymphoma (AITL)
    • Follicular T cell lymphoma
    • Nodal peripheral T-cell lymphoma with TFH phenotype There should be a documented expression of minimum two TFH markers among this panel of markers: CD10, CXCL13, PD1, ICOS and BCL6 by the tumoral cells by immunohistochemistry. Biopsy at relapse or progression is not mandatory, but highly encouraged on a surgical or needle core biopsy, and diagnostic tissue should be available for central pathology review and for ancillary molecular studies.

    Local pathology report should be reviewed by the sponsor's medical monitor prior to enrollment.

  5. ECOG performance status 0 to 3
  6. Relapsed (after partial or complete response) or refractory AITL after at least one line of systemic therapy (there is no mandatory resting period after the previous treatment as long as the biochemistry and hematology labs meet the inclusion criteria as below.)
  7. Meet the following lab criteria:

    • ANC ≥ 1,5 x 109/L (≥ 1 x 109/L if BM involvement by lymphoma)
    • Platelet ≥ 75 x 109/L (≥ 50 x 109/L if BM involvement by lymphoma)
    • Hemoglobin ≥ 8 g/dL.
  8. Anticipated life expectancy at least 3 months
  9. At least one measurable lesion on CT that is greater than 1.5 cm in the longest diameter for nodal lesions and greater than 1.0 cm in the longest diameter for extranodal lesions. The lesion must be measurable in two perpendicular dimensions. Patients with only cutaneous disease will be excluded.
  10. Female patient of childbearing potential (FCBP) may participate, providing she meets the following conditions:

    Have two negative pregnancy tests as verified by the investigator prior to starting study treatment: serum pregnancy test at Screening and negative serum or urine pregnancy test (investigator's discretion) within 72 hours prior to starting treatment with study treatment (Cycle 1 Day 1). She must agree to ongoing pregnancy testing during the study (before beginning each subsequent cycle of treatment), and 28 days after the last study drug administration. This applies even if the patient practices complete abstinence from heterosexual contact.

    Agrees to practice true abstinence (which must be reviewed monthly and source documented) or agrees to the use of highly effective methods of contraception from 28 days prior to starting study treatment, and must agree to continue using such precautions during study treatment (including dose interruptions) and for up to 6 months after the last study drug administration. True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation, symptomthermal, post ovulation methods) and withdrawal are not acceptable methods of contraception. Cessation of contraception after this point should be discussed with a responsible physician.

    Agrees to abstain from breastfeeding during study participation and for at least 6 months after the last study drug administration.

    A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months).

  11. Male patient must either practice true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agrees to avoid fathering a child, to use highly effective methods of contraception, male condom plus spermicide during sexual contact with a pregnant female or a female of childbearing potential (even if he has undergone a successful vasectomy), from starting dose of IP (cycle 1 Day 1), including dose interruptions through 6 months after receipt of the last study drug administration.

    Furthermore, male patient must agree to not give semen or sperm during study drug therapy and for a period of 1 year after end of study drug therapy.

  12. For EU countries, patient covered by a social security system

Exclusion Criteria:

  1. Clinical evidence of central nervous system(CNS) involvement by lymphoma. Patients with suspicion of CNS involvement must undergo neurologic evaluation and CT/MRI of head and lumbar puncture to exclude CNS disease.
  2. Any significant medical conditions, laboratory abnormality or psychiatric illness likely to interfere with participation in this clinical study (according to the investigator's decision)
  3. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment)
  4. Known Human Immunodeficiency Virus (HIV) or Hepatitis C Virus (HCV) infection, or evidence of active Hepatitis B Virus (HBV) infection defined as:

    • HBs Ag positive
    • HBs Ag negative, anti-HBs antibody positive and/or anti-HBc antibody positive with detectable viral DNA
  5. Impaired renal function (calculated MDRD or Cockcroft-Gault Creatinine Clearance < 30 ml/min) or impaired liver function tests (Serum total bilirubin level > 2.0 mg/dl [34 μmol/L] (except in case of Gilbert's Syndrome, or documented liver or pancreatic involvement by lymphoma), Serum transaminases (AST or ALT) > 3 upper normal limits) unless they are related to the lymphoma.
  6. Active malignancy other than the one treated in this research. Prior history of malignancies, other than low risk MDS or CMML (with less than 5% blasts in bone marrow), unless the patient has been free of the disease for ≥ 3 years. However, patients with the following history/concurrent conditions are allowed:

    1. Basal or squamous cell carcinoma of the skin
    2. Carcinoma in situ of the cervix
    3. Carcinoma in situ of the breast
    4. Incidental histologic finding of prostate cancer (T1a or T1b) using the tumor, nodes, metastasis [TNM] clinical staging system
  7. Treatment with any investigational drug within 5 half-lives before planned first cycle of study treatment and during the study. Ongoing medically significant adverse events from previous treatment, regardless of the time period.
  8. Prior exposure to azacitidine and/ or any other demethylating agent (eg, decitabine)
  9. Prior exposure to planned study treatment investigator's choice therapy (eg, prior exposure to gemcitabine is an exclusion if gemcitabine is the investigator's choice therapy prior to randomization)
  10. Concurrent use of corticosteroids unless the patient is on a stable or decreasing dose for ≥ 1 week prior to informed consent form signature
  11. Knowing or suspected hypersensitivity to active substance or to any of the excipients.
  12. Pregnant, planning to become pregnant, or lactating woman
  13. Candidate for hematopoietic stem cell transplantation
  14. History of active inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis), celiac disease (ie, 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 oral azacitidine and/or predispose the patient to an increased risk of gastrointestinal toxicity per investigator's decision. Any condition causing inability to swallow tablets.
  15. Significant active cardiac disease within the previous 6 months, including:

    • New York Heart Association (NYHA) class IV congestive heart failure
    • Unstable angina or angina requiring surgical or medical intervention; and/or
    • Myocardial infarction
  16. Person deprived of his/her liberty by a judicial or administrative decision
  17. Adult person under legal protection

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): NCT03703375


Contacts
Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@celgene.com

Locations
Japan
National Hospital Organization Nagoya Medical Center Not yet recruiting
Nagoya, Aichi, Japan
National Cancer Center Hospital East Not yet recruiting
Kashiwa, Chiba, Japan
Kyushu University Hospital Not yet recruiting
Higashi-ku, Fukuoka, Japan
University of Tsukuba Hospital Not yet recruiting
Tsukuba, Ibataki, Japan
Tokai University Hospital Not yet recruiting
Isehara, Kanagawa, Japan
National University Corporation Tohoku University Hospital Not yet recruiting
Sendai, Miyagi, Japan
Kindai University Hospital Not yet recruiting
Osaka-Sayama, Osaka, Japan
Saitama Medical University International Medical Center Not yet recruiting
Hidaka, Saitama, Japan
National Cancer Center Hospital Not yet recruiting
Chuo-ku, Tokyo, Japan
The Cancer Institute Hospital of Japanese Foundation For Cancer Research Not yet recruiting
Koto-ku, Tokyo, Japan
Sponsors and Collaborators
Celgene
Investigators
Study Director: Toru Sasaki, MD Celgene

Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT03703375     History of Changes
Other Study ID Numbers: OA-CL-LYM-LYSARC-13134C
U1111-1220-8294 ( Registry Identifier: WHO )
2017-003909-17 ( EudraCT Number )
First Posted: October 12, 2018    Key Record Dates
Last Update Posted: October 12, 2018
Last Verified: October 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Celgene:
CC-486
Azacitidine
Angioimmunoblastic
T Cell Lymphoma
Lymphoma

Additional relevant MeSH terms:
Lymphoma
Lymphoma, T-Cell
Immunoblastic Lymphadenopathy
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Lymphadenopathy
Gemcitabine
Azacitidine
Romidepsin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic