A Combination of Rituximab and CC-99282 As Front-line Therapy for Older Frail Patients with Diffuse Large B-cells Non-Hodgkin Lymphoma Evaluated with a Simplified Geriatric Assessment (sGA): a Phase II Study of the Fondazione Italiana Linfomi (FIL)

Prospective, multicenter, single arm, phase II study, to evaluate the efficacy of the combination rituximab-golcadomide as a chemo free approach in a population of older patients with new diagnosis of DLBCL, defined as frail according to a sGA evaluation and not candidate for the standard R-CHOP (or R-CHOP like) treatments.

This is a prospective, multicenter, phase II study, in older patients affected by DLBCL defined as frail according to sGA and previously untreated.

All patients will receive an induction phase with a combination of golcadomide, rituximab and only at cycle 1 dexamethasone, for a maximum number of 6 cycles of 28 days.

Response assessment is planned after 4 and after 6 cycles for identification of non-responding patients. Patients achieving at least a PR at the interim restaging and after 6th cycle will complete therapy as planned, while patients with stable and progressive disease will discontinue protocol treatment and will be addressed to an alternative regimen.

At the end of the 6th cycle of induction (EOI), involved site radiotherapy is allowed on PET positive sites.

At EOI (end of induction), if the patient reached at least a partial response (≥PR), a consolidation phase was planned with golcadomide, for a maximum of 6 cycles of 28 days.

During consolidation phase, an interim check for response will be performed after the completion of 3 cycles in order to early identify progressive disease. Patients with progressive disease will stop protocol treatment and will be treated at physician discretion.

End of treatment response will be evaluated within 4-6 weeks after the last cycle of consolidation (or the last study medication administration).

All patients will be monitored during follow up for 24 months, every 3 months for the first year and every 6 months for the second year.

Patients experimenting progression at any time will be considered as treatment failures and will be followed-up for survival until the end of the study.

Baseline and EOT 18FDG PET/CT or CT scan including pre-contrast phase (only if PET/CT is not performed) will be evaluated for sarcopenia assessment.

Quality of life (QoL) evaluation is planned at study entry and at established timepoints during and after treatment and follow-up.

Eligibility Criteria:
Inclusion Criteria:

1. Able to provide written informed consent form approved by the National Ethics Committee (NEC) prior to the initiation of any screening or study- specific procedures and able to understand and to comply with the requirements of the study and the schedule of assessments.
2. Histologically documented diagnosis of DLBCL as defined in the 5th edition of the World Health Organization (WHO) classification (2022)
3. Previously untreated
4. Frail patients defined as follows (Appendix A-D): Age ≥ 80 years: activity of daily living (ADL) \< 6 residual functions and/or Instrumental activity of daily living (IADL) \< 8 residual functions and/or cumulative illness rating scale (CIRS) \> 5 comorbidities of grade 2 and/or one or more comorbidities of grade 3-4
5. Patient not eligible to anthracycline-based chemotherapy
6. Ann Arbor Stage I - IV (Appendix E)
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 3 (Appendix F)
8. At least one site of measurable nodal disease at baseline \[≥ 1.5 cm\] in the longest transverse diameter as determined by CT scan
9. Adequate hematological counts defined as follows:

   * WBC \> 2.5 x 109/L with ANC \> 1.0 x 109/L unless due to bone marrow involvement by lymphoma
   * Platelet count ≥ 75 x 109/L unless due to bone marrow involvement by lymphoma
   * Hemoglobin ≥ 10 g/dL unless anemia related to active lymphoma
10. Adequate renal function defined as creatinine clearance ≥ 30 mL/min (Appendix G). The same CrCl cutoff applies in case of documented renal involvement by lymphoma
11. Adequate hepatic function per local laboratory reference range, unless secondary to lymphoma, as follows:

    * Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.0 x ULN
    * Bilirubin ≤ 2 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin, i.e. mild and chronic hemolysis)
12. Subject must be able to adhere to the study visit schedule and other protocol requirements
13. Subject must be able to swallow capsules or tablets
14. Life expectancy ≥ 3 months
15. Male subjects must practice complete abstinence when this is in line with the usual lifestyle (periodic abstinence is not permitted) or agree to use specified contraceptive methods (barrier contraception: condom) during sexual contact with a female of childbearing potential while participating in the study, for at least 28 days following investigational product discontinuation, even if he has undergone a successful vasectomy. Furthermore, they do not have to donate sperm during the study and for at least 28 days after receiving the last dose of study drug. If applicable, male subjects must receive study specific Pregnancy Prevention Plan (PPP).

Exclusion Criteria:

1. Histological diagnosis different from DLBCL
2. Central nervous system (CNS) involvement with lymphoma
3. Severe heart failure (NYHA grado III-IV and/or LVEF \< 45%), liver disease Child Pugh C, history of interstitial lung disease, non-infectious pneumonitis, pulmonary fibrosis, or pulse oximetry of \< 92% while breathing room air, or any other clinical condition that would preclude participation in the study or compromise ability to give informed consent
4. Any history of other active malignancies within 5 years prior to study entry, except for adequately treated in situ carcinoma of the cervix uterine, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin, previous malignancy confined and surgically resected with curative intent
5. Gastrointestinal dysfunction that may affect drug absorption (eg, gastric bypass surgery, gastrectomy) or any other malabsorption condition
6. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:

   1. Uncontrolled and/or active systemic infection (viral, bacterial or fungal), including active ongoing infection from SARS-CoV-2
   2. Chronic or acute hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV i.e. hepatitis B surface (HBs) antigen (Ag) negative, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative, may participate; patients with positive anti-HBc antibody from previous infection or inactive carriers are eligible only with HBV-DNA negative and with concomitant treatment with Lamivudine or Tenofovir
   3. Patients with presence of HCV antibody are eligible only if PCR negative for HCV-RNA
7. Human immunodeficiency virus (HIV) seropositivity
8. Absence of caregivers in non-autonomous patients
9. Allergy or intolerance to the active or inactive ingredients of study drugs