FIL_POLARDHAP: R-DHAP vs POLA-R-DHAP Followed by Autologous Transplant as First Salvage Treatment in Patient With Relapsed or Refractory Diffuse Large B Cell Lymphoma

Sponsor

Fondazione Italiana Linfomi - ETS (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05966233

Collaborator

Roche Pharma AG (Industry)

150

Enrollment

Locations

Arms

Anticipated Duration (Months)

3.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Prospective, multicenter, open label, phase II randomized clinical trial in DLBCL patients relapsed or refractory to first line R-chemo, aged 18-70 years and candidate to autologous transplant. Patients will be randomized 1:1 to received 4 cycles of R-DHAP or R-DHAP plus Polatuzumab Vedotin as induction treatment plus autologous transplant.

Condition or Disease	Intervention/Treatment	Phase
Diffuse Large B Cell Lymphoma Refractory Diffuse Large B-cell Lymphoma Recurrent	Drug: R-DHAP Drug: Pola-R-DHAP	Phase 2

Detailed Description

PET-CT scan performed after induction be centrally review for disease response. Responding patients (CR) after induction will be addressed to receive Autologous Stem Cells Transplantation (ASCT) consolidation as per local guidelines. Patients achieving PR can proceed with ASCT or with a 3rd-line treatment, according to the physician judgment. Patients in SD/PD will be diverted to salvage strategies.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

150 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase II Randomized Clinical Trial to Evaluate the Efficacy of the Addition of Polatuzumab Vedotin to Standard Chemotherapy R-DHAP (POLA-R-DHAP) as Induction Pre-transplantation Therapy in Patients With Diffuse Large B-Cell Lymphoma Refractory/Relapsed After First Line Treatment.

Anticipated Study Start Date :

Oct 1, 2023

Anticipated Primary Completion Date :

Oct 1, 2028

Anticipated Study Completion Date :

Oct 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: R-DHAP R-DHAP x4 + autologous transplant/salvage treatment (based on centrally review response)	Drug: R-DHAP Rituximab 375 mg/m2 IV on D0 or D1 Dexamethasone 40 mg/day IV or PO on D1-4 Ara-C 2 g/m2 IV on D2 (2 doses every 12h) or D2 and D3 Cisplatin 100 mg/ m2 IV on D1
Experimental: Pola-R-DHAP Pola-R-DHAP x4 + autologous transplant/salvage treatment (based on centrally review response)	Drug: Pola-R-DHAP Polatuzumab Vedotin 1.8 mg/kg IV on D1 Rituximab 375 mg/m2 IV on D0 or D1 Dexamethasone 40 mg/day IV or PO on D1-4 Ara-C 2 g/m2 IV on D2 (2 doses every 12h) or D2 and D3 Cisplatin 100 mg/ m2 IV on D1

Arm

Intervention/Treatment

Active Comparator: R-DHAP

R-DHAP x4 + autologous transplant/salvage treatment (based on centrally review response)

Drug: R-DHAP

Rituximab 375 mg/m2 IV on D0 or D1 Dexamethasone 40 mg/day IV or PO on D1-4 Ara-C 2 g/m2 IV on D2 (2 doses every 12h) or D2 and D3 Cisplatin 100 mg/ m2 IV on D1

Experimental: Pola-R-DHAP

Pola-R-DHAP x4 + autologous transplant/salvage treatment (based on centrally review response)

Drug: Pola-R-DHAP

Polatuzumab Vedotin 1.8 mg/kg IV on D1 Rituximab 375 mg/m2 IV on D0 or D1 Dexamethasone 40 mg/day IV or PO on D1-4 Ara-C 2 g/m2 IV on D2 (2 doses every 12h) or D2 and D3 Cisplatin 100 mg/ m2 IV on D1

Outcome Measures

Primary Outcome Measures

Progression free survival (PFS) [From treatment start up to 30 months (6 months treatment period and 24 months of follow-up)]
Time between the randomization to first documentation of recurrence, progression or death from any cause

Secondary Outcome Measures

Event-Free Survival (EFS) [From treatment start up to 30 months (6 months treatment period and 24 months of follow-up)]
Time between the randomization to any treatment failure, including disease progression, or discontinuation of treatment for any reason (e.g., disease progression, toxicity, patient preference, initiation of a new treatment without documented progression) or death from any cause.
Complete response rate (CRR) [From treatment start up to end of treatment evaluation (about 6 months)]
CRR will be defined according to Response Criteria for NHL with PET (Lugano 2014). CRR will include only patients who achieved a CR and will be evaluated on assessed patients and on all treated patients, considering patients without a response assessment (due to any reason) as non-responders.
Overall response rate (ORR) [From treatment start up to end of treatment evaluation (about 6 months)]
ORR will be defined as the proportion of patients who have a partial or complete response to therapy (CR+PR).
Overall Survival (OS) [From treatment start up to 30 months (6 months treatment period and 24 months of follow-up)]
Time between randomization to death from any cause.
Incidence and severity of AEs [From start to end of induction treatment evaluation (about 3 months)]
Incidence and severity of AEs in R-DHAP vs POLA-R-DHAP according to latest CTCAE criteria during induction immunochemotherapy
Adequate stem cells mobilization [From beginning of 2nd cycle to end of induction treatment evaluation (about 2 months)]
Adequate stem cells mobilization will be defined by the target cell harvesting of 3 x 10^6 CD34+ cells/kg
Autologous consolidation feasibility [At time of end of treatment assessment (up to 6 months from treatment begin)]
Proportion of patients receiving autologous consolidation after POLA-R-DHAP vs R-DHAP

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically documented diagnosis of Diffuse Large B-Cell Lymphoma Not otherwise specified (DLBCL-NOS) as defined in the 2022 edition of the World Health Organization (WHO) classification; are also admitted documented diagnosis of:

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL)
Epstein-barr virus (EBV)-associated DLBCL
Double-hit and triple-hit high grade B-cell lymphomas (HGBL DH/TH)
High-grade B-cell lymphoma, NOS (HGBL)
Transformed FL not previously untreated
Follicular large B-cell lymphoma (FLBL, former follicular 3b)

Known availability of biopsy material (at relapse/refractory or previous most recent). Re-biopsy highly encouraged even if not mandatory. Central pathology review required, but not mandatory for registration and treatment start;
Relapse or refractoriness after the first line R-chemo (R-CHOP o similar). Previous treatment with polatuzumab containing regimen is allowed as per clinician judgment;
CAR-T not indicated or unavailable;
Age 18-70 years. sGA mandatory for patients 65-70 years old: only category FIT admitted [20] (see Appendix A);
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 if not related to lymphoma disease (see Appendix B);
Measurable disease ≥ 1.5 cm in longest diameter, and measurable in 2 perpendicular dimensions;
Normal blood count defined as: neutrophils at least 1.500/mmc, platelets at least 75.000/mmc, haemoglobin at least 8,0 g/dL with transfusion independence, unless abnormalities due to underlying disease (bone marrow involvement), at the moment of signing informed consent;
Adequate liver function, assessed by baseline laboratory values; the increase to up to 2.5 ULN for transaminases and up to 1.5 ULN for bilirubin admitted for cases with documented liver involvement by lymphoma;
Adequate renal function defined as creatinine clearance ≥ 40 mL/min (Cockcroft-Gault formula; see Appendix C)
Subjects HBsAg negative but positive for antibodies to hepatitis B core antigen with undetectable HBV-DNA measured by real-time polymerase chain reaction (PCR).
Women of childbearing potential (WOCBP) and men must agree to use effective contraception if sexually active. Females of childbearing potential and males with female partners of reproductive potential should be advised to use effective contraception while receiving polatuzumab vedotin and for 9 months after the last dose of polatuzumab vedotin for female patients and for 6 months after the last dose of polatuzumab vedotin for male patients with female partners of reproductive potential. A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include but are not limited to hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for continuous 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth control method (failure rate of less than 1%) e.g. intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner. The use of condoms by male patients is required (even if surgically sterilized, i.e., status post vasectomy) unless the female partner is permanently sterile. Full sexual abstinence is admitted when this is in line with the preferred and usual lifestyle of the subject, for the same time period planned for other methods of birth control (see above). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods for the female partner) and withdrawal are not acceptable methods of contraception
WOCBP must have a negative serum (beta-human chorionic gonadotropin [b-hCG]) or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study;
Life expectancy > 6 months;
Subject understands and voluntarily signs an informed consent form approved by the National Ethics Committee prior to the initiation of any screening or study-specific procedures;
Subject must be able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria:

Any histology other than DLBCL
Primary mediastinal lymphoma (PMBCL)
Known central nervous system lymphoma
Known history of severe allergic or anaphylactic reactions to human, humanized, chimeric, or murine monoclonal antibodies
Contraindication to any drug in the chemotherapy regimen
Left ventricular ejection fraction (LVEF) < 50%
Neuropathy ≥ grade 2
Subject is:

Seropositive for hepatitis B, defined by a positive test for hepatitis B surface antigen [HBsAg]. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (HBsAb positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR
Known to be seropositive for hepatitis C. EXCEPTION: Patients with presence of HCV antibody, but PCR negative for HCV-RNA are eligible
Positive for human immunodeficiency virus (HIV) infection

Any uncontrolled active systemic infection requiring intravenous (IV) antibiotics
History of stroke or intracranial hemorrhage within the past 6 months.
History of clinically relevant liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, rheumatologic, hematologic, psychiatric, or metabolic disturbances
Clinically significant cardiovascular disease
Major surgical intervention prior 4 weeks to enrollment if not due to lymphoma and/or other disease life-threatening that can compromise chemotherapy treatment
Prior malignancies other than lymphoma in the last 5 years with exception of currently treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix
Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety
If female, the patient is pregnant or breast-feeding
Patients participating in other clinical studies

Contacts and Locations

Locations

	Site	City	Country
1	A.O. SS. Antonio e Biagio e Cesare Arrigo, S.C. Ematologia	Alessandria	Italy
2	AOU Ospedali Riuniti, Clinica di Ematologia	Ancona	Italy
3	Azienda Ospedaliera S.Giuseppe Moscati, S.C. Ematologia e Trapianto emopoietico	Avellino	Italy
4	IRCCS Centro di Riferimento Oncologico di Aviano, Divisione di Oncologia e dei Tumori immuto-correlati	Aviano	Italy
5	IRCCS Istituto Tumori Giovanni Paolo II, U.O.C Ematologia	Bari	Italy
6	Cliniche Humanitas Gavazzeni, Oncologia	Bergamo	Italy
7	ASST Spedali Civili di Brescia, Ematologia	Brescia	Italy
8	Ospedale Businco, SC Ematologia e CTMO	Cagliari	Italy
9	Fondazione del Piemonte per l'Oncologia - IRCCS, Ematologia	Candiolo	Italy
10	Arnas Nuovo Ospedale Garibaldi Nesima, U.O.C. Ematologia	Catania	Italy
11	A.O. S. Croce e Carle, S.C. di Ematologia e Trapianto di Midollo Osseo	Cuneo	Italy
12	Azienda Ospedaliera Universitaria Careggi, Unitа funzionale di Ematologia	Firenze	Italy
13	Ospedale Vito Fazzi, Ematologia	Lecce	Italy
14	ASST Ovest Milanese - Legnano, U.O.C. Ematologia	Legnano	Italy
15	ASST Grande Ospedale Metropolitano Niguarda, SC Ematologia	Milano	Italy
16	Istituto Scientifico San Raffaele, Unitа Linfomi - Dipartimento Oncoematologia	Milano	Italy
17	Ospedale Maggiore Policlinico - Fondazione IRCCS Ca Granda, Ematologia	Milano	Italy
18	Fondazione IRCCS San Gerardo dei Tintori, Ematologia	Monza	Italy
19	AOU Maggiore della Caritа di Novara, SCDU Ematologia	Novara	Italy
20	Presidio ospedaliero "A. TORTORA", U.O. Onco-ematologia	Pagani	Italy
21	A.O. Ospedali Riuniti Villa Sofia-Cervello, Divisione di Ematologia	Palermo	Italy
22	Ospedale S. Maria della Misericordia, Ematologia	Perugia	Italy
23	P.O. Spirito Santo di Pescara, UOS Dipartimentale - Centro di diagnosi e Terapia dei linfomi	Pescara	Italy
24	Ospedale Guglielmo da Saliceto, U.O.Ematologia	Piacenza	Italy
25	AOU Pisana, U.O. Ematologia	Pisa	Italy
26	A.O.R. "San Carlo", U.O. Ematologia	Potenza	Italy
27	Ospedale delle Croci, Ematologia	Ravenna	Italy
28	Azienda Unitа Sanitaria Locale-IRCCS - Arcispedale Santa Maria Nuova, Ematologia	Reggio Emilia	Italy
29	AO San Giovanni Addolorata, S.C. Ematologia	Roma	Italy
30	AO Sant Andrea, Ematologia	Roma	Italy
31	Policlinico Umberto I - Universitа "La Sapienza", Istituto Ematologia -Dipartimento di Medicina Traslazionale e di Precisione	Roma	Italy
32	Policlinico Universitario Campus Bio-Medico, Ematologia - Trapianto cellule staminali - Medicina Trasfusionale e Terapia cellulare	Roma	Italy
33	Istituto Clinico Humanitas, U.O. Ematologia	Rozzano	Italy
34	AOU Senese, U.O.C. Ematologia	Siena	Italy
35	A.O.U. Citta della Salute e della Scienza di Torino, Ematologia Universitaria	Torino	Italy
36	A.O.U. Citta della Salute e della Scienza di Torino, S.C.Ematologia	Torino	Italy
37	Ospedale Ca Foncello, S.C di Ematologia	Treviso	Italy
38	A.O.C. Panico, U.O.C Ematologia e Trapianto	Tricase	Italy
39	Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI), SC Ematologia	Trieste	Italy
40	AOU Integrata di Verona, U.O. Ematologia	Verona	Italy