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

• Azacitidine (Drug), also known as CC-486: Azacitidine
• Romidepsin (Drug): Romidepsin
• Gemcitabine (Drug): Gemcitabine

Primary outcomes

• Progression Free Survival (PFS) Based on Local Assessment [From randomization up to documented disease progression or death, whichever occurs first (up to approximately 15 months)]: PFS is defined as the time from randomization into the study to the first observation of documented disease progression (local assessment using Lugano Response Criteria 2014) or death due to any cause, whichever occurs first. If a participant has not progressed or died, PFS will be censored at the time of last visit with adequate assessment. C2 censoring rules were used per US FDA guidance 2015. Progression will be determined as per Response criteria for lymphoma: Lugano classification.

Secondary outcomes

• Overall Survival (OS) [From randomization up to the date of death or date last known alive (up to approximately 27 months)]: Overall survival is defined as the time from the date of randomization to the date of death from any cause. OS was censored at the last date that the participant was known to be alive.
• Progression Free Survival (PFS) Based on IRC Assessment [From randomization up to documented disease progression or death, whichever occurs first (up to approximately 37 months)]: PFS based on Independant Review Committee (IRC) is defined as the time from randomization into the study to the first observation of documented disease progression (reviewed assessment by IRC using Lugano Response Criteria 2014) or death due to any cause. If a patient has not progressed or died, PFS will be censored at the time of last visit with adequate assessment per FDA's guidance 2015 Table C2. Progression will be determined as per Response criteria for lymphoma: Lugano classification.
• Overall Response Rates (ORR) [Response rate will be measured after Cycle 3, after Cycle 6 (up to approximately 5.5 months)]: Overall response rates are the percentage of complete response (CR) and partial response (PR) per local assessment. Assessment of response will be based on Lugano Response Criteria 2014 for the radiologic response (CT based), the metabolic response (PET-CT based) and the best response between radiologic and metabolic response. Measurements occurred after Cycle 3, after Cycle 6, and at permanent treatment discontinuation. PR is defined as Score 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size and ≥ 50% decrease in SPD of up to 6 target measurable nodes and extranodal sites. CR is defined as target nodes/nodal masses regressed to ≤ 1.5 cm in LDi, no extralymphatic sites of disease, and Score 1, 2, or 3 with or without a residual mass on the 5 Point Scale. The Lugano 5-point scale is 1, no uptake above background; 2, uptake mediastinum; 3, uptake mediastinum but liver; 4, uptake moderately liver; 5, uptake markedly higher than liver and/or new lesions.
• Complete Response Rate (CRR) [Response rate will be measured after Cycle 3, after Cycle 6 (up to approximately 5.5 months)]: Complete response rate is the percentage of CR (complete metabolic response or CT-based CR) per local assessment before receiving any subsequent anti-lymphoma therapy. Assessment will be based on Lugano Response Criteria 2014 for the radiologic response (CT based), the metabolic response (PET-CT based) and best response between radiologic and metabolic response. Measurements occurred after Cycle 3, Cycle 6, and treatment discontinuation. PR is defined as Score 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size and ≥ 50% decrease in SPD of up to 6 target measurable nodes and extranodal sites. CR is defined as target nodes/nodal masses regressed to ≤ 1.5 cm in LDi, no extralymphatic sites of disease, and Score 1, 2, or 3 with or without a residual mass. The Lugano 5-point scale is 1, no uptake above background; 2, uptake mediastinum; 3, uptake mediastinum but liver; 4, uptake moderately liver; 5, uptake markedly higher than liver and/or new lesions.
• Duration of Response (DOR) [From randomization to the date of first documented disease progression, relapse (local assessment) or death from any cause (up to approximately 27 months)]: Duration of response is defined as the time from attainment of complete response (CR) or partial response (PR) per local assessment to the date of first documented disease progression, relapse (local assessment) or death from any cause. Participants alive and free of progression will be censored at their last visit with adequate assessment.CR: complete metabolic response or computed tomography (CT)-based CR; PR: partial metabolic response or CT-based PR before subsequent anti-lymphoma therapy.
• Time to Response (TTR) [From randomization to the date of attainment of complete response (CR) or partial response (PR) until end of treatment (up to approximately 37 months)]: Time to response is defined as the time from randomization to the date of attainment of complete response (CR) or partial response (PR) per local assessment until end of treatment. If a participant is not responder, time to response will be censored at the time of last visit with adequate assessment. CR: complete metabolic response or computed tomography (CT)-based CR; PR: partial metabolic response or CT-based PR before subsequent anti-lymphoma therapy.
• Progression Free Survival 2 (PFS2) on Local Assessment [From randomization to objective tumor progression on next-line treatment or death from any cause (up to approximately 27 months)]: PFS2 based on local assessment is defined as the time from randomization to objective tumor progression on next-line treatment or death from any cause. Participants without next-line therapy who did not die and participants who did not relapse or not die after next-line therapy will be censored at the last adequate tumor assessment date.
• Mean Change in Minimal Important Differences (MIDs) of the EORTC QLQ-C30 Health-related Quality-of-Life Domain Scores [At baseline and on Day 1 of each cycle up to treatment discontinuation (up to approximately 27 months)]: The minimal important difference (MID) is the size of difference in Quality-of-Life score that is considered relevant (i.e. warranting a change in treatment or examinations). The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQC30) subscale values are the lower threshold for MID over time, based on within-group mean change. QLQ-C30 has 5 functional scales (physical, role, emotional, cognitive, social), 3 symptom scales (fatigue, nausea/vomiting, pain), a global health status / quality of life (QoL) scale, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties). Each scale was scored on a range from 0 to 100. Higher scores represent a higher response level. Note that a high score for global health status or for a functional scale represents a high or healthy level of functioning, but a high score for a symptom scale/item represents a high level of symptomatology/problems.

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• Progression Free Survival (PFS) Based on Local Assessment (Primary), Median, Months: Oral Azacitidine 5.6 (2.66 to 7.26); Investigators Choice Therapy Combined (Romidepsin, Bendamustine, Gemcitabine) 2.8 (1.87 to 4.83) (p 0.0541)
• Overall Survival (OS) (Secondary), Median, Months: Oral Azacitidine 18.4 (12.88 to 31.47); Investigators Choice Therapy Combined (Romidepsin, Bendamustine, Gemcitabine) 10.3 (4.24 to 13.50) (p 0.0166)
• Progression Free Survival (PFS) Based on IRC Assessment (Secondary), Median, Months: Oral Azacitidine 4.2 (2.66 to 5.88); Investigators Choice Therapy Combined (Romidepsin, Bendamustine, Gemcitabine) 3.2 (2.10 to 4.83) (p 0.2139)
• Overall Response Rates (ORR) (Secondary), Number, Percentage of participants: Oral Azacitidine 33.3 (19.6 to 49.5); Investigators Choice Therapy Combined (Romidepsin, Bendamustine, Gemcitabine) 43.2 (28.3 to 59.0)
• Complete Response Rate (CRR) (Secondary), Number, Percentage of participants: Oral Azacitidine 11.9 (4.0 to 25.6); Investigators Choice Therapy Combined (Romidepsin, Bendamustine, Gemcitabine) 22.7 (11.5 to 37.8)
• Duration of Response (DOR) (Secondary), Number, Percentage of participants: Oral Azacitidine 10.4 (2.56 to NA); Investigators Choice Therapy Combined (Romidepsin, Bendamustine, Gemcitabine) 3.4 (2.00 to NA)
• Time to Response (TTR) (Secondary), Median, Months: Oral Azacitidine 3 (3 to 6); Investigators Choice Therapy Combined (Romidepsin, Bendamustine, Gemcitabine) 2.7 (1 to 4)
• Progression Free Survival 2 (PFS2) on Local Assessment (Secondary), Median, Months: Oral Azacitidine 11.0 (6.44 to 18.89); Investigators Choice Therapy Combined (Romidepsin, Bendamustine, Gemcitabine) 6.7 (3.52 to 9.56)
• Mean Change in Minimal Important Differences (MIDs) of the EORTC QLQ-C30 Health-related Quality-of-Life Domain Scores (Secondary)

Adverse events

Time frame: Participants were assessed for all-cause mortality from their enrollment to study completion, (up to approximately 37 months). SAEs and Other AEs were assessed from first dose to 28 days following last dose (up to approximately 38 months)

Serious adverse events by term

Other adverse events by term

42 more terms not shown.

• Results publication: Dupuis J, Bachy E, Morschhauser F, Cartron G, Fukuhara N, Daguindau N, Casasnovas RO, Snauwaert S, Gressin R, Fox CP, d'Amore FA, Staber PB, Tournilhac O, Bouabdallah K, Thieblemont C, Andre M, Rai S, Ennishi D, Gkasiamis A, Nishio M, Fornecker LM, Delfau-Larue MH, Sako N, Mule S, de Leval L, Gaulard P, Tsukasaki K, Lemonnier F. Oral azacitidine compared with standard therapy in patients with relapsed or refractory follicular helper T-cell lymphoma (ORACLE): an open-label randomised, phase 3 study. Lancet Haematol. 2024 Jun;11(6):e406-e414. doi: 10.1016/S2352-3026(24)00102-9. PMID 38796193

• Study Protocol and Statistical Analysis Plan (PDF, 2022-04-22)

• Bristol-Myers Squibb, Study director, Bristol-Myers Squibb