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VITALIZE

Une Étude de Phase 2b Ouverte, Multicentrique, Randomisée en Groupes Parallèles selon un Schéma à Deux Étapes, sur le Traitement Immunothérapeutique DPX-Survivac en Association avec le Pembrolizumab avec et sans Régime Intermittent à Faible Dose de Cyclophosphamide, chez des Sujets Atteints de Lymphome Diffus à Grandes Cellules B Récidivant/Réfractaire (VITALIZE).

Critères d'inclusion :

Subjects are eligible to be included in the study only if all of the following criteria apply:


1. Adults ≥ 18 years of age who are willing and able to provide written informed consent


2. Have an ECOG performance status of ≤ 1. Subjects with an ECOG performance status of 2 may be enrolled with Medical Monitor approval. The number of subjects with an ECOG performance status of 2 will be capped at approximately 20% of any treatment arm and must be reserved prior to consenting the subject.


3. Pathologically confirmed diagnosis of DLBCL, as defined by the 2016 World Health Organization classification including DLBCL NOS high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, Epstein-barr virus (EBV) positive DLBCL, and T cell rich B cell lymphoma (TCRBCL). Subjects with DLBCL transformed from indolent lymphoma (except for Richter’s transformation) are eligible.


4. Subjects must have progressive disease following at least two (2) lines of prior systemic therapy for DLBCL; prior treatment must have included an anthracycline and rituximab (or another CD20-targeted agent).


5. Subjects must be ASCT or CAR-T ineligible according to the Investigator as defined by at least one of the following:
a. One or more co-morbidities, poor performance status and/or advanced age that in the opinion of the Investigator makes the subject medically unfit to receive ASCT or CAR-T therapy
b. Active disease following induction and salvage chemotherapy or inadequate stem cell/CAR-T mobilization and/or apheresis
c. Failure of prior ASCT or CAR-T
d. Unwilling to undergo ASCT or CAR-T treatment


6. Have at least one bi-dimensionally measurable lesion per Lugano (2014)1 as assessed by local imaging. For subjects staged with PET-CT, focal uptake in nodal and extranodal sites that is in keeping with lymphoma, according to the distribution and/or CT characteristics, is considered involvement with lymphoma, including but not limited to, spleen, liver, bone, and thyroid.


7. Willing to provide pre-treatment and on-treatment tumor biopsy tissue.
a. Pre-treatment: fresh biopsy preferred but archival may be submitted if there has been no exposure to systemic anti-cancer or localized radiation at site of biopsy between date of biopsy and analysis.

i. Confirmation of availability of the pre-treatment tumor biopsy or eligible archival tissue and request to obtain material must be made during screening period.
b. On-treatment at study D70, unless deemed unsafe by the Investigator.


8. Demonstrate adequate organ function* as defined as:
Test
Required Laboratory Value
Hematologic
Absolute neutrophil count (ANC)
≥ 1,000 /mcL
Platelets
≥ 50,000 / mcL, unless due to disease under study
Hemoglobin
≥ 8 g/dL without packed red blood cell (pRBC) transfusion within the prior 2 weeks, unless due to disease under study. Subjects can be on stable dose of erythropoietin (≥ approximately 3 months).
Renal
Calculated Creatinine Clearance (Cockcroft-Gault)
≥ 30 mL/min
Hepatic
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN OR
≤ 5 X ULN for subjects with liver involvement of
DLBCL
Serum total bilirubin
≤ 1.5 X ULN Unless history of Gilbert’s disease or due to disease under study OR
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
Other
LDH
LDH ˂ 5 times the upper limit of normal
*Adequate organ function should be confirmed within 72 hours prior to receiving the first dose of study medication (D0).


9. Life expectancy > 3 months.


10. A subject is eligible to participate if they are not pregnant, not breastfeeding, and at least one of the following conditions applies:
a. For females:
i. Not a woman of childbearing potential (WOCBP), or
ii. A WOCBP who agrees to follow contraceptive guidance during the treatment period and for at least 210 days after the last dose of study treatment.
b. Males who agree to follow contraceptive guidance during the treatment period and for at least 210 days after the last dose of study treatment


11. Ability to comply with protocol requirements.
 

Critères de non inclusion :

Subjects are excluded from the study if any of the following criteria apply:

 

1. Primary CNS lymphoma or active secondary CNS involvement and/or lymphomatous meningitis. CNS imaging and cerebrospinal fluid sampling are not mandatory in the absence of a clinical suspicion of lymphomatous involvement of the CNS.

 

2. Chemotherapy, immunotherapy, major surgery, or investigational agent treatment within 28 days of D0 or 5 half-lives whichever is shorter, except as noted:

a. Radiotherapy within 14 days of day 0. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.

b. Autologous stem cell transplant (ASCT) within ˂100 days prior to D0.
c. Chimeric antigen receptor T cell (CAR-T) therapy within ˂28 days prior to D0
All treatment related toxicities related to prior therapies must be recovered to < Grade 1 or baseline, except for organ function criteria mandated by the inclusion criteria. Subjects with Grade 2 alopecia, peripheral neuropathy endocrine-related AEs requiring treatment or hormone replacement are eligible.


3. The following prior medications/procedures are exclusionary.
a. Allogeneic stem cell transplant or allogeneic CAR-T therapy or solid organ transplant
b. Prior therapy with anti-survivin therapy
c. Anti-PD-1, anti-PD-L1, anti-PD-L2, or CTLA-4 agent
d. Chronic systemic steroid therapy (doses exceeding 10 mg daily prednisone equivalent) or other immunosuppressive therapy within 7 days of D0. Single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular) are permitted.
e. Prescribed or over-the-counter probiotic treatments
f. Live-attenuated vaccine within 30 days of planned start of study therapy


4. Disorders that might interfere with study treatment including:
a. History of (non-infectious) pneumonitis that required steroids or current pneumonitis
b. Unable to swallow tablets, malabsorption syndrome, short-gut syndrome, gastroparesis or any other gastrointestinal disease or dysfunction (e.g., nausea/vomiting/diarrhea that is CTCAE ≥ Grade 2) that could interfere with absorption of study treatment
c. Acute or chronic skin, microvascular disorders, and/or edema or lymphedema that could interfere with subcutaneous injection of DPX-Survivac or subsequent assessment of potential skin reactions.


5. Diagnosis of immunodeficiency disorder or history of active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is permitted.


6. Clinically severe cardiovascular disease (e.g., NYHA Class III or IV CHF, uncontrolled angina; history of myocardial infarction within 6 months or unstable angina or stroke within 30 days of study entry; uncontrolled hypertension; or clinically significant arrhythmias not controlled by medication).


7. Uncontrolled significant active infections.
a. Subjects who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. Note: Subjects should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention.
b. Subjects with HCV are eligible if HCV viral load is undetectable at screening. Note: Subjects must have completed curative anti-viral therapy at least 4 weeks prior to randomization.
c. HIV infected subjects must be on anti-retroviral therapy (ART) and have a well-controlled HIV infection/disease defined as:
i. Subjects on ART must have a CD4+ T-cell count >350 cells/mm3 at time of screening
ii. Subjects on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks prior to screening
iii. Subjects on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to D0.

iv. HIV-infected subjects cannot have a history of Kaposi sarcoma and/or Multicentric Castleman Disease.


8. Prior history of malignancy other than eligible lymphoma sub-types, unless the subject has been free of the disease for ≥ 2 years prior to the start of study treatment. Subjects with the following neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ, cervical intraepithelial neoplasia, and organ-confined prostate cancer with no evidence of progressive disease.


9. Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients.


10. Known intolerance to DPX-Survivac and/or CPA, or chemical derivatives or any of the excipients.


11. A WOCBP who has a positive pregnancy test (within 72 hours) prior to treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.


12. Any other concurrent severe and/or uncontrolled concomitant medical condition that could compromise participation in the study (e.g., clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection).


13. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.