Clinical trial NCT05300282: Study of Atezolizumab Plus BEGEV Regimen in Relapsed or Refractory Hodgkin's Lymphoma Patients
Official title: A Phase I/II B (randomized Controlled) Study of Atezolizumab Combined to BEGEV Regimen As First Salvage Treatment in Patients with Relapsed or Refractory Hodgkin's Lymphoma Candidate to Autologous Stem-cell Transplantation
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Relapsed or Refractory Hodgkin's Lymphoma
Keywords: Hodgkin's lymphoma
atezolizumab
BEGEV
phase I/II b study
relapsed
refractory
MTD
Lead sponsor: Fondazione Italiana Linfomi - ETS
Sponsor class: OTHER
Collaborators: name: Roche Pharma AG
First posted: 2022-03-29
Enrollment: 122
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: The phase I part is aimed at determining the MTD of atezolizumab when combined with BEGEV schedule. Atezolizumab dosing starts at 1200 mg and decreases in the successive cohort to the dose of 840 mg and 600 mg to reach MTD which will be used in the phase II part where patients will be randomized in 2 arms: arm A will receive the BEGEV regimen followed by ASCT for patients achieving CR and arm B will receive combination treatment with Atezolizumab and BEGEV regimen followed for patients reaching CR by ASCT plus a consolidation with 6 doses of atezolizumab at 1200 mg every 4 weeks.
Primary purpose: TREATMENT

Brief summary: The phase I part (safety assessment of the combination treatment) is aimed at determining the MTD of atezolizumab when combined with BEGEV schedule.

6-18 patients enrolled in this part will be treated with atezolizumab in combination with BEGEV regimen every 3 weeks for 4 cycles.

Patients without a DLT in the first cycle and without disease progression after cycle 2, will undergo stem cell mobilization with 3-4 cycle of A-BEGEV + granulocyte colony-stimulating factor (G-CSF) and subsequently receive a myeloablative therapy followed by ASCT.

The phase IIb part (expansion cohort) plans to randomize 122 patients in two arms (A and B, 61 per arm):

1. arm A will receive the BEGEV regimen followed by ASCT for patients achieving CR.
2. arm B will receive combination treatment with Atezolizumab and BEGEV regimen followed for patients reaching CR by ASCT plus a consolidation with 6 doses of atezolizumab at 1200 mg every 4 weeks.

After the last treatment date of the last patient (LPLT), the phase IIb will be ended. A long term follow up will start, in order to better assess patients' prognosis. All evaluable patients from phase I and phase IIb study will enter in the long term follow up phase and will be followed for 18 months.

Detailed description: The phase I part (safety assessment of the combination treatment) is aimed at determining the MTD of atezolizumab when combined with BEGEV schedule.

6-18 patients enrolled in this phase will be treated with atezolizumab in combination with BEGEV regimen every 3 weeks for 4 cycles.

Patients without a DLT in the first cycle and without disease progression after cycle 2, will undergo stem cell mobilization with 3-4 cycle of A-BEGEV + granulocyte colony-stimulating factor (G-CSF) and subsequently receive a myeloablative therapy followed by ASCT.

Patients with documented CR following ASCT will receive a consolidation therapy with atezolizumab as single agent every 4 weeks for 6 doses, starting preferably between 60 and 90 days, but ≥ 60 days and not \> 120 days after autografting. In patients not previously radiotreated, adjuvant radiotherapy (RT) should be planned during consolidation treatment within the start of second consolidation dose, according to clinician's judgment and response assessment. RT will be administered at 30-36 Gy on sites of initial bulky disease or on single PET positive residual site.

Patients reaching PR after four cycles of atezolizumab combined with BEGEV or with documented PR after ASCT may continue the study protocol according to the physician judgment.

Dosing starts at 1200 mg and decreases in the successive cohort to the dose of 840 mg and 600 mg, according to Flow chart A. in the section 6 of the protocol.

In the consolidation phase atezolizumab will be administered at dose of 1200 mg every 4 weeks for 6 doses without dose reduction, but only delay or discontinuation.

Patients included in the cohort developing DLT, withdraw the protocol due to toxicity and continue the treatment according to good clinical practice.

For patients included in the cohort of MTD, monitoring and collection of AEs will be continuous during induction, consolidation treatment and follow-up.

The phase IIb part (expansion cohort) plans to randomize 122 patients in two arms (A and B, 61 per arm):

1. arm A will receive the BEGEV regimen followed by ASCT for patients achieving CR.
2. arm B will receive combination treatment with Atezolizumab and BEGEV regimen followed for patients reaching CR by ASCT plus a consolidation with 6 doses of atezolizumab at 1200 mg every 4 weeks.

In patients not previously radiotreated, adjuvant RT should be planned for both patients in arm A and arm B according to clinician's judgment and response assessment. RT will be administered at 30-36 Gy on sites of initial bulky disease or on single PET positive residual site.

Patients reaching PR after four induction cycles (atezolizumab combined with BEGEV or BEGEV alone) or with documented PR after ASCT may continue the study protocol according to the physician judgment.

After the last treatment date of the last patient (LPLT), the phase IIb will be ended. A long term follow up will start, in order to better assess patients' prognosis. All evaluable patients from phase I and phase IIb study will enter in the long term follow up phase and will be followed for 18 months. Disease status, survival outcome, secondary primary malignancies and late toxicity will be collected every 6 months until patient withdrawal of consent, lost to follow up and patient's death. Long term follow-up phase will end 18 months after the end of phase IIb.

Eligibility criteria: Inclusion Criteria:

* 18-60 years old (upper limit valid only for phase I).
* Histologically confirmed cHL, at first disease relapse or refractory to a first-line treatment or with documented persistent disease at interim positron emission tomography (PET) performed after 2 cycles of first line (ABVD/ABVD like/BEACOPP).
* Only one prior systemic therapy for Hodgkin's lymphoma (HL).
* First disease relapse or refractory to a first-line treatment.
* Eligibility for ASCT.
* Performance status (PS) ≤ 2 on the Eastern Cooperative Oncology Group (ECOG) scale.
* Adequate haematological function, unless abnormalities due to underlying disease, at the moment of signing informed consent, defined as follows:

  * neutrophils \> or = 1.500/mmc and
  * platelets \> or = 75.000/mmc and
  * haemoglobin \> or = 8,0 g/dL with transfusion independence
* Capacity and willingness to adhere to study visit schedule and specific protocol procedures.
* Compliance with effective contraception without interruption, according to physician's judgement, from 28 days before treatment start up to at least 6 months after treatment discontinuation, agreeing not to donate semen/eggs during treatment and for at least 6 months after last treatment dose.

Exclusion Criteria:

* More than one prior systemic therapy for HL.
* Presence of autoimmune disease (based on medical history): systemic lupus erythematosus, autoimmune thyroid disease (Hashimoto's thyroiditis, Basedow's disease), Sjögren's syndrome, glomerulonephritis, multiple sclerosis, rheumatoid arthritis, vasculitis, idiopathic pulmonary fibrosis (includine bronchiolitis obliterans organizing pneumonia) and inflammatory bowel disease (Crohn's disease, ulcerative colitis).
* Previous skin toxicity (i.e. Steven-Johnson Sdr, severe skin reactions.
* Prior allogeneic stem cell transplantation or prior solid organ transplant.
* History of active tubercolosis.
* History of leptomeningeal disease.
* Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment.
* Central nervous system (CNS) involvement by lymphoma.
* Major surgery (excluding any lymph node biopsy) within 28 days prior to signing informed consent.
* Seropositivity for HBV or evidence of active infection. The following categories may be considered for the study:

  * HBsAg positive with HBV DNA \< 2000 UI/ml (inactive carriers); HBV DNA \> 2000 UI/ml is criteria of exclusion
  * HBsAg negative but HBsAb positive
  * HBsAg negative but HBcAb positive HBsAg positive with HBV DNA \< 2000 UI/ml and HBsAg negative but HBcAb positive will be eligible for the study only if they accept to receive antiviral prophylaxis for all the period of treatment and at least for 12 months after the end of therapy. Treatment should be stopped in case of hepatitis reactivation. - Seropositivity for HCV. Patients with presence of HCV antibody are eligible only if PCR result are negative for HCV RNA
* Seropositivity for HIV.
* Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail bed) or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics except if for tumor fever) within 2 weeks of the start of Cycle 1.
* Life expectancy lower than 6 months.
* Prior history of malignancies, other than HL, unless the patient has been free for at least 5 years (exceptions: localized non-melanoma skin cancer ad carcinoma in situ of the cervix).
* Any of the following laboratory abnormalities: liver enzymes (AST/SGOT and/or ALT/SGPT) \> 3 fold the upper limit of normal (except of liver involvement by lymphoma); total bilirubin \> 1.5 mg/dL (except for patients with known Gilbert's disease or biliary tree compression by lymphoma masses); creatinine clearance \< 30 mL/min.
* Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina.
* History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
* Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
* Pregnancy or breastfeeding, or unwillingness to comply with adequate contraception (one negative pregnancy test within 14 days prior to initiation of study treatment required).
* Any serious medical condition, laboratory abnormality or psychiatric illness that would prevent the patient from signing the informed consent or which may place the patient at unacceptable risk if participating in the study.

Exception to Exclusion:

* Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study.
* Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
* Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:

  * Rash must cover \< 10% of body surface area
  * Disease is well controlled at baseline and requires only low-potency topical corticosteroids
  * No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
* Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease (COPD) exacerbation) are eligible for the study.

Primary outcomes:
measure: For Phase I part: evaluation of the maximum tolerated dose (MTD) of the atezolizumab.
timeFrame: During first cycle of treatment based on atezolizumab in combination with BEGEV in phase I study. Maximum time frame 17 months.
measure: For Phase II part: evaluation of the Complete Response Rate (CRR) before ASCT.
timeFrame: From initial treatment based on Atezolizumab and BEGEV to intensification treatment with ASCT. Time frame 4 months.
Secondary outcomes:
measure: For Phase II part: evaluation of the overall response rate (ORR), partial response (PR), stable disease (SD) and progression disease (PD) rates.
timeFrame: The best response between the date of beginning of therapy and the last restaging. Time frame 14 months.
measure: For Phase II part: evaluation of the rate of partial response (PR) converted to Complete Response (CR).
timeFrame: At the end of consolidation treatment with atezolizumab in the experimental arm. Time Frame 14 months.
measure: For Phase II part: evaluation of the peripheral blood stem-cell mobilization
timeFrame: At the end of treatment based on atezolizumab and BEGEV. Time Frame 3 months.
measure: For Phase II part: evaluation of engraftment after ASCT
timeFrame: Between 30 and 60 days after ASCT: Time Frame 5 months.
measure: For Phase II part: evaluation of duration of response (DoR).
timeFrame: From the CR to the date of relapse or progression or last scheduled visit. Time frame 50 months.
measure: For Phase II part: evaluation of Progression Free Survival (PFS) for all patients.
timeFrame: From beginning therapy to progression or relapse disease or death. Time frame 50 months.
measure: For Phase II part: evaluation of OS.
timeFrame: From the beginning of therapy to death for any cause or last scheduled visit. Time frame 50 months.
measure: For Phase II part: evaluation of safety and tolerability of atezolizumab and BEGEV.
timeFrame: From the beginning of treatment to death or lost to follow-up or last scheduled visit. Time frame 50 months.
measure: For Phase II part: evaluation of he correlation of quantitative baseline PET parameters
timeFrame: From the beginning of treatment to death or lost to follow-up or last scheduled visit. Time frame 50 months.
Other outcomes:
Locations:
city: Candiolo
country: Italy
facility: Ematologia - Fondazione del Piemonte per l'Oncologia - IRCCS
state: Turin
city: Alessandria
country: Italy
facility: S.C. Ematologia - A.O. SS. Antonio e Biagio e Cesare Arrigo
city: Avellino
country: Italy
facility: S.C. Ematologia e Trapianto emopoietico - Azienda Ospedaliera S.Giuseppe Moscati
city: Aviano
country: Italy
facility: Divisione di Oncologia e dei Tumori immuto-correlati - IRCCS Centro di Riferimento Oncologico di Aviano
city: Bari
country: Italy
facility: U.O.C Ematologia - IRCCS Istituto Tumori Giovanni Paolo II
city: Barletta
country: Italy
facility: Ematologia - Ospedale "Monsignor Raffaele Dimiccoli"
city: Brescia
country: Italy
facility: Ematologia - ASST Spedali Civili di Brescia
city: Lecce
country: Italy
facility: Ematologia - Ospedale Vito Fazzi
city: Milan
country: Italy
facility: Ematologia - Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
city: Milan
country: Italy
facility: SC Ematologia - ASST Grande Ospedale Metropolitano Niguarda
city: Pagani
country: Italy
facility: U.O. Onco-ematologia - Presidio ospedaliero "A. TORTORA"
city: Palermo
country: Italy
facility: Divisione di Ematologia - A.O. Ospedali Riuniti Villa Sofia-Cervello
city: Pavia
country: Italy
facility: Div. di Ematologia - IRCCS Policlinico S. Matteo di Pavia
city: Perugia
country: Italy
facility: Ematologia - Ospedale S. Maria della Misericordia
city: Reggio Emilia
country: Italy
facility: Ematologia - Azienda Unitа Sanitaria Locale-IRCCS - Arcispedale Santa Maria Nuova
city: Roma
country: Italy
facility: Ematologia - Ospedale S. Camillo
city: Roma
country: Italy
facility: Istituto Ematologia -Dipartimento di Medicina Traslazionale e di Precisione - Policlinico Umberto I - Università "La Sapienza"
city: Rozzano
country: Italy
facility: U.O. Ematologia - Istituto Clinico Humanitas
city: Terni
country: Italy
facility: S.C. Oncoematologia - A.O. S. Maria di Terni
city: Torino
country: Italy
facility: S.C.Ematologia - A.O.U. Città della Salute e della Scienza di Torino
city: Trieste
country: Italy
facility: Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) - SC Ematologia
Study officials:
affiliation: U.O. Ematologia - Istituto Clinico Humanitas - Rozzano - ITALY
name: Armando Santoro, MD
role: PRINCIPAL_INVESTIGATOR
References: