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

Phase 2

Withdrawn

• Conditions: Diffuse Large B Cell Lymphoma Refractory; Diffuse Large B-cell Lymphoma Recurrent
• Interventions: Drug: R-DHAP; Drug: Pola-R-DHAP

• Registration Number: NCT05966233
• Lead Sponsor: Fondazione Italiana Linfomi - ETS

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.

Detailed Description

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.

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 Timeline

• Study First Submitted: 2023-07-21
• Study First Submitted QC: 2023-07-21
• Study First Posted: 2023-07-28
• Study Start: 2024-01
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-20
• Last Update Posted: 2024-05-21
• Primary Completion: 2029-01
• Study Completion: 2029-01

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

1. 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)

2. 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;

3. 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;

4. CAR-T not indicated or unavailable;

5. Age 18-70 years. sGA mandatory for patients 65-70 years old: only category FIT admitted [20] (see Appendix A);

6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 if not related to lymphoma disease (see Appendix B);

7. Measurable disease ≥ 1.5 cm in longest diameter, and measurable in 2 perpendicular dimensions;

8. 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;

9. 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;

10. Adequate renal function defined as creatinine clearance ≥ 40 mL/min (Cockcroft-Gault formula; see Appendix C)

11. Subjects HBsAg negative but positive for antibodies to hepatitis B core antigen with undetectable HBV-DNA measured by real-time polymerase chain reaction (PCR).

12. 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

13. 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;

14. Life expectancy > 6 months;

15. 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;

16. Subject must be able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria

1. Any histology other than DLBCL

2. Primary mediastinal lymphoma (PMBCL)

3. Known central nervous system lymphoma

4. Known history of severe allergic or anaphylactic reactions to human, humanized, chimeric, or murine monoclonal antibodies

5. Contraindication to any drug in the chemotherapy regimen

6. Left ventricular ejection fraction (LVEF) < 50%

7. Neuropathy ≥ grade 2

8. 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

9. Any uncontrolled active systemic infection requiring intravenous (IV) antibiotics

10. History of stroke or intracranial hemorrhage within the past 6 months.

11. History of clinically relevant liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, rheumatologic, hematologic, psychiatric, or metabolic disturbances

12. Clinically significant cardiovascular disease

13. Major surgical intervention prior 4 weeks to enrollment if not due to lymphoma and/or other disease life-threatening that can compromise chemotherapy treatment

14. 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

15. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety

16. If female, the patient is pregnant or breast-feeding

17. Patients participating in other clinical studies

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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.
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.
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
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.
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
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

Trial Locations

Locations (37)

ASST Grande Ospedale Metropolitano Niguarda, SC Ematologia; 🇮🇹 Milano, Italy

P.O. Spirito Santo di Pescara, UOS Dipartimentale - Centro di diagnosi e Terapia dei linfomi; 🇮🇹 Pescara, Italy

A.O. SS. Antonio e Biagio e Cesare Arrigo, S.C. Ematologia; 🇮🇹 Alessandria, Italy

Azienda Ospedaliera S.Giuseppe Moscati, S.C. Ematologia e Trapianto emopoietico; 🇮🇹 Avellino, Italy

AOU Ospedali Riuniti, Clinica di Ematologia; 🇮🇹 Ancona, Italy

Cliniche Humanitas Gavazzeni, Oncologia; 🇮🇹 Bergamo, Italy

Ospedale delle Croci, Ematologia; 🇮🇹 Ravenna, Italy

AO San Giovanni Addolorata, S.C. Ematologia; 🇮🇹 Roma, Italy

A.O.U. Citta della Salute e della Scienza di Torino, Ematologia Universitaria; 🇮🇹 Torino, Italy

AOU Senese, U.O.C. Ematologia; 🇮🇹 Siena, Italy

A.O.U. Citta della Salute e della Scienza di Torino, S.C.Ematologia; 🇮🇹 Torino, Italy

Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI), SC Ematologia; 🇮🇹 Trieste, Italy

IRCCS Centro di Riferimento Oncologico di Aviano, Divisione di Oncologia e dei Tumori immuto-correlati; 🇮🇹 Aviano, Italy

IRCCS Istituto Tumori Giovanni Paolo II, U.O.C Ematologia; 🇮🇹 Bari, Italy

ASST Spedali Civili di Brescia, Ematologia; 🇮🇹 Brescia, Italy

Fondazione del Piemonte per l'Oncologia - IRCCS, Ematologia; 🇮🇹 Candiolo, Italy

Arnas Nuovo Ospedale Garibaldi Nesima, U.O.C. Ematologia; 🇮🇹 Catania, Italy

A.O. S. Croce e Carle, S.C. di Ematologia e Trapianto di Midollo Osseo; 🇮🇹 Cuneo, Italy

Azienda Ospedaliera Universitaria Careggi, Unitа funzionale di Ematologia; 🇮🇹 Firenze, Italy

Ospedale Vito Fazzi, Ematologia; 🇮🇹 Lecce, Italy

ASST Ovest Milanese - Legnano, U.O.C. Ematologia; 🇮🇹 Legnano, Italy

Istituto Scientifico San Raffaele, Unitа Linfomi - Dipartimento Oncoematologia; 🇮🇹 Milano, Italy

Ospedale Maggiore Policlinico - Fondazione IRCCS Ca Granda, Ematologia; 🇮🇹 Milano, Italy

A.O. Ospedali Riuniti Villa Sofia-Cervello, Divisione di Ematologia; 🇮🇹 Palermo, Italy

Ospedale S. Maria della Misericordia, Ematologia; 🇮🇹 Perugia, Italy

Ospedale Guglielmo da Saliceto, U.O.Ematologia; 🇮🇹 Piacenza, Italy

AOU Pisana, U.O. Ematologia; 🇮🇹 Pisa, Italy

A.O.R. "San Carlo", U.O. Ematologia; 🇮🇹 Potenza, Italy

Azienda Unitа Sanitaria Locale-IRCCS - Arcispedale Santa Maria Nuova, Ematologia; 🇮🇹 Reggio Emilia, Italy

Istituto Clinico Humanitas, U.O. Ematologia; 🇮🇹 Rozzano, Italy

A.O.C. Panico, U.O.C Ematologia e Trapianto; 🇮🇹 Tricase, Italy

AO Sant Andrea, Ematologia; 🇮🇹 Roma, Italy

AOU Maggiore della Caritа di Novara, SCDU Ematologia; 🇮🇹 Novara, Italy

Fondazione IRCCS San Gerardo dei Tintori, Ematologia; 🇮🇹 Monza, Italy

Policlinico Universitario Campus Bio-Medico, Ematologia - Trapianto cellule staminali - Medicina Trasfusionale e Terapia cellulare; 🇮🇹 Roma, Italy

Policlinico Umberto I - Universitа "La Sapienza", Istituto Ematologia -Dipartimento di Medicina Traslazionale e di Precisione; 🇮🇹 Roma, Italy

Ospedale Ca Foncello, S.C di Ematologia; 🇮🇹 Treviso, Italy