| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory Diffuse Large B-Cell Lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed/Refractory Diffuse Large B-Cell Lymphoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10012819 |
| E.1.2 | Term | Diffuse large B-cell lymphomas |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the objective response rate (ORR) in each of the study arms. |
|
| E.2.2 | Secondary objectives of the trial |
• To determine the safety profile of the treatment in each of the study arms
• To determine the duration of response (DOR) in each of the study arms
• To determine the time to response in each of the study arms
• To determine the Progression-Free Survival in each of the study arms
• To determine the disease control rate (DCR) in each of the study arms
• To determine the complete response (CR) rate in each of the study arms
• To assess patient reported outcomes (PRO) on quality of life in each of the study arms |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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; at least one prior treatment must have included an anthracycline (unless contra-indicated, e.g.pre existing cardiac condition) 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. Unable to receive CAR-T therapy due to financial, geographic, or insurance issues (Note: does not apply in France)
e. 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: (please see protocol)
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 120 days (210 days in France only) 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 |
|
| E.4 | Principal exclusion criteria |
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
Note: 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.
Please refer to protocol for exclusion criteria #10, 11, 12 and 13. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response rate centrally evaluated per Lugano (2014) and measured by the number of subjects per arm achieving a best response of partial or complete response (PR+CR) during the 2-year treatment period. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Rate of Adverse Events using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0;
• Duration of response evaluated per Lugano (2014) and measured by the time between first documentation of objective response (CR or PR) until first radiologic evidence of confirmed progression;
• Time to response starting from D0 until first documentation of objective response (CR or PR) per Lugano (2014);
• Progression Free Survival starting from D0 until first radiologic evidence of confirmed progression per Lugano (2014);
• Disease control rate evaluated per Lugano (2014) and measured by the number of subjects per arm achieving a best response of stable disease, partial or complete response (SD+PR+CR) during the 2-year treatment period;
• Complete response evaluated per Lugano (2014) and measured by the number of subjects per arm achieving a best response of complete response (CR) during the 2year treatment period;
• Patient reported outcomes collected using validated, disease-specific, quality of life questionnaires. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| DPX-Survivac, Pembrolizumab, Cyclophosphamide versus DPX-Survivac, Pembrolizumab |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| New Zealand |
| Australia |
| Canada |
| France |
| Hungary |
| Poland |
| Romania |
| Serbia |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Completion of the Survival Follow-up period for the last patient treated in the study. Completion of follow-up for the last patient will occur when the last patient in the study has been followed for up to 2 years after their End of Treatment Visit, has withdrawn consent, has been withdrawn from the study by the Investigator, has died, or has been lost to follow-up, whichever occurs first. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 48 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 48 |
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