Framework for Optimizing, Refining, and Unifying Management of HSCT in Pediatric ALL.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ospedale Pediatrico Bambino Gesu

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

24 Dec 2025 → ongoing

Decision date (initial)

2025-11-17

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Amgen · Neovii Biotech GmbH · Novartis

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety

The overall objective of the FORUM-2 platform trial is to optimize the role of HSCT in ALL by reducing treatment-related toxicity while preserving the essential graft-versus-leukemia (GVL) effect.

This ambitious goal is pursued by addressing the multiple objectives and endpoints of the different studies. The primary objectives of each of the different sub-study are reported below:
- R1 To demonstrate that a TBI regimen of 8 Gy TBI combined with VP16 (experimental arm) is non-inferior to a conditioning regimen of 12 Gy TBI combined with VP16 (standard arm) in terms of survival outcomes in patients aged >2 to ≤25 years undergoing HSCT from either an HLA-identical sibling donor (MSD) or an HLA-matched unrelated donor (MD).
- R2 To compare the efficacy of ruxolitinib in combination with corticosteroids versus corticosteroids alone in terms of ORR at Day 28 in subjects with grade II-IV treatment-naïve aGVHD
- S1 To compare the outcome of HSCT from HLA-mismatched donors after either PTCy or TCRαβ/CD19 depletion GvHD prophylaxis in ALL children, adolescents, and young adults up to 25 years old.
- O1 To evaluate the predictive power of EASIX for NRM in all patients enrolled in the FORUM 2 trial undergoing HSCT in ALL
- O2 To evaluate the outcome in patients transplanted with an ABO major mismatch according to the standard procedure in the treatment center
- P1 To evaluate the efficacy of up to four cycles of blinatumomab as post-HSCT maintenance therapy in reducing cumulative incidence of relapse in children under two years of age with CD19-positive B-ALL undergoing HSCT after a chemotherapy-based conditioning regimen.

Conditions and MedDRA coding

Framework for Optimizing, Refining, and Unifying Management of HSCT in Pediatric ALL

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Inclusion Criteria applicable to All the patients • Male and female patients with allogenic transplant indication for ALL, as determined by national frontline protocols, including but not limited to: o AIEOP-BFM ALL 2017 or 2025 o ALLTogether o ALL-IC o IntReALL 2020 o ESPhall-COG o Interfant 2021 o Other recognized national frontline protocols. • Age ≥3 months to ≤25 years at the time of HSCT. • Patients must be in complete remission (with <5% blasts and absence of leukemia cells in extramedullary sites) prior to undergoing HSCT. • Selected donor must be either a matched donor (matched donor category includes 9/10 identical siblings and 10/10 or 9/10 HLA-matched unrelated donors) or a mismatched family donor (≤8/10 HLA match). Both bone marrow or peripheral blood stem cell grafts are permitted. Cord blood is permitted, as well, provided that the unit is at least 6/8 HLA matched and with a cryopreserved cellularity of at least 3x107 nucleated cells/Kg recipient body weight. • Female patients of childbearing potential must have a negative pregnancy test at screening, and all patients must agree to adhere to effective contraception during the study period. • Written study informed consent and/or assent from the patient and/or the parent, or guardian at the time of screening. • No history of other malignancies.
2. R1 Sub-Study Inclusion Criteria • Subjects enrolled in the FORUM2 platform trial. • Patients ≥2 years to ≤ 25 years of age at the time of informed consent. • Selected donor must be a matched donor (matched donor category includes 10/10 identical siblings and 10/10 or 9/10 HLA-matched unrelated donors). Both bone marrow or peripheral stem cell grafts are permitted. Related donor cord blood is permitted, as well, if the unit has a cryopreserved cellularity of at least 3x107 nucleated cells/Kg recipient body weight. • Written study informed consent and/or assent from the patient and the parent or guardian at the time of screening. • Fulfilment of the inclusion criteria of the FORUM 2 platform trial
3. R2 Sub-Study Inclusion Criteria • Subjects enrolled in the FORUM2 platform trial. • Patients ≥3 months to < 18 years of age at the time of informed consent. • Patients who have received an unmanipulated allogeneic bone marrow or peripheral blood transplant from a matched donor (matched donor category includes ≥9/10 related or unrelated donors). Recipients of either TBI-based (irrespective of the intensity) or chemo- conditioning regimens are eligible. • Clinically suspected grade II to IV aGVHD as per MAGIC criteria, occurring after allo-HSCT. Biopsy confirmation of aGvHD is recommended whenever possible but is not mandatory. Enrollment should not be delayed awaiting biopsy or pathology results and, in cases where a biopsy cannot be obtained or is clinically contraindicated, clinical suspicion of acute GVHD by the treating physician is sufficient, provided that alternative diagnoses are adequately ruled out. • Evidence of myeloid engraftment (ANC ≥ 0.5 × 109/L for 3 consecutive days). Use of growth factor supplementation is allowed. • Able to swallow and retain oral medication. • Written study informed consent and/or assent from the patient and the parent or guardian at the time of screening
4. S1 Sub-Study Inclusion Criteria • Subjects enrolled in the FORUM2 platform trial. • Patients ≥3 months to ≤25 years of age at the time of informed consent. • Selected donor must be a mismatched family donor (≤8/10 HLA match). • GvHD prophylaxis based on either in-vivo PTCy or ex vivo αβ T-Cell depletion. • Use of the conditioning regimens specified in the specific study. • Written study informed consent and/or assent from the patient and the parent or guardian at the time of screening
5. P1 Sub-Study Inclusion Criteria • Subjects enrolled in the FORUM2 platform trial. • Patients < 2 years of age at HSCT • Evidence of CD19 expression on leukemia blasts prior to HSCT. Previous treatment with blinatumomab and any other CD19-directed immunotherapy during front-line treatment before the allograft is not considered an exclusion criterion. • Patients who have received an allogeneic bone marrow or peripheral blood HSCT from a matched donor (matched donor category includes ≥9/10 related or unrelated donors) or mismatched related donors (i.e., HLA-hapoidentical donor). • Morphological bone marrow complete remission at time of enrollment, independently from MRD levels (both before and after HSCT) and independently from the presence of recurrent molecular lesions, such as KMT2A rearrangements. • No evidence of CNS active disease (i.e., CNS1) or any extramedullary localization of leukemia cells at time of study enrolment. Patients with previous CNS leukemia involvement are eligible if CNS was successfully treated prior to enrollment. • Written study informed consent and/or assent from the patient and/or the parent, or guardian at the time of screening
6. O1 Sub-Study Inclusion Criteria • Subjects enrolled in the FORUM2 platform trial. • Patients ≥3 months to ≤25 years of age at the time of informed consent. • Written study informed consent and/or assent from the patient and the parent or guardian at the time of screening
7. O2 Sub-Study Inclusion Criteria • Subjects enrolled in the FORUM2 platform trial. • Patients ≥3 months to ≤25 years of age at the time of informed consent. • Patients expected to receive bone marrow allografts with ABO major incompatibility from either matched donors or mismatched family donors • Written study informed consent and/or assent from the patient and the parent or guardian at the time of screening

Exclusion criteria 7

1. Exclusion Criteria applicable to all the patients • Patients < 3 months and > 25 years of age at the time of HSCT. • Patients not in complete morphological remission at the time of enrollment. • Patients with an initial diagnosis of Non-Hodgkin Lymphoma (NHL). • Patients with ALL as a secondary malignancy. • Patients with a history of previous autologous or allogeneic HSCT (prior allogeneic transplantation is permitted for subjects receiving post-transplant interventions, such as those enrolled in the R2 and P1 study, provided that this is their first allogeneic HSCT). • Female patients who are pregnant or breast feeding. • Fertile male or female patients of childbearing potential who do not agree to abstinence or, if sexually active, do not agree to the use of contraception. • Active clinically uncontrolled bacterial, fungal, parasitic, or viral infection. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no physical or radiographic signs of infection progression are present. • Active HBV or HCV infection that requires treatment, or at risk for HBV reactivation (ie, positive HBsAg). Subjects with negative HbsAg and positive total HB core antibody may be included if HBV DNA is undetectable at the time of screening. Subjects who are positive for HCV antibody are eligible only if polymerase chain reaction test is negative for HCV RNA. Subjects whose immune status is unknown or uncertain must have results confirming immune status before enrollment. Prior serology results are acceptable for determining eligibility. • Known human immunodeficiency virus infection (HIV). • Significant respiratory disease including patients who are on mechanical ventilation or who have resting O2 saturation <90% by pulse-oximetry on room-air. • Presence of severely impaired renal function (confirmed within 72 hrs prior to study treatment start) defined by: o Glomerular Filtration Rate (GFR) < 30 mL/min/1.73 m2 using estimated creatinine clearance calculated by updated bedside Schwartz equation or Cockroft Gault equation • Or o Renal dialysis requirement • Clinically significant or uncontrolled cardiac disease including any of the following: o - Uncontrolled hypertension o - New York Heart Association Class III or IV congestive heart failure o - Clinically significant cardiac arrhythmias • Severe hepatic insufficiency, defined by any of the following: o Child-Pugh Class C liver disease o AST (aspartate aminotransferase) or ALT (alanine aminotransferase) levels > 5 times the upper limit of normal (ULN), unless attributable to GvHD o Total bilirubin > 3.0 mg/dL, unless attributable to GvHD o INR (International Normalized Ratio) ≥ 1.7 o Clinical evidence of hepatic encephalopathy or ascites • Presence of severe concomitant constitutional disease that precludes treatment as per protocol, based on the investigator’s judgment. Examples include but are not limited to: Down syndrome with severe comorbidities, significant cardiac malformations, metabolic disorders affecting treatment feasibility. • Underlying or current medical or psychiatric condition that, in the opinion of the Investigator, would interfere participation in the study, pose a significant risk to the patient or interfere with interpretation of study data. • Karnofsky or Lansky performance score <50%, indicating significant functional impairment. • Patients who are unwilling or unable to comply with study procedures, including follow-up requirements and treatment schedules.
2. R1 Sub-Study Exclusion Criteria • Patients not enrolled in the FORUM 2 platform trial (independently of the reason). • Patients <2 years or > 25 years of age at the time of informed consent. • Use of an unrelated cord blood unit or a mismatched family donor as the stem cell source • Patients who received CNS irradiation at a dose of 18 Gy within 12 months prior to HSCT, if the combined total dose from prior CNS irradiation and planned TBI conditioning will exceed 24 Gy. • Patient meets one or more of the exclusion criteria defined in the FORUM 2 platform trial
3. R2 Sub-Study Exclusion Criteria • Patients not enrolled in the FORUM 2 platform trial (independently of the reason) • Patients <3 months of age or ≥ 18 years. • Patients transplanted from mismatched family donor (≤8/10 HLA match) or related/unrelated CB. • Patients having received any prior systemic treatment of aGvHD except for a maximum 72h of prior systemic corticosteroid therapy after the onset of acute GvHD. Patients are allowed to have received prior GvHD prophylaxis which is not counted as systemic treatment (as long as the prophylaxis was started prior to the diagnosis of aGvHD) • Clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome with both acute and chronic GvHD features • Failed prior allogeneic HSCT, including previous primary or secondary graft failure • Acute GvHD occurring after non-scheduled donor leukocyte infusion (DLI) administered for pre-emptive treatment of malignancy recurrence. • Presence of overt relapse of primary malignancy, requiring either additional treatment after allogeneic HSCT or rapid immune suppression tapering/withdrawal • Any corticosteroid therapy for indications other than GVHD at doses > 1 mg/kg per day methylprednisolone (or prednisone equivalent) within 7 days of randomization. • Cholestatic disorders, or unresolved sinusoidal obstructive syndrome/veno-occlusive disease of the liver (defined as persistent bilirubin abnormalities not attributable to aGvHD and ongoing organ dysfunction). • Known allergies, hypersensitivity, or intolerance to any of the study medications, excipients, or similar compounds.
4. S1 Sub-Study Exclusion Criteria • Patients not enrolled in the FORUM 2 platform trial (independently of the reason) • Patients <3 months or > 25 years of age at the time of informed consent. • Any type of GvHD prophylaxis other than in-vivo PTCy or ex vivo αβ T-Cell depletion
5. P1 Sub-Study Exclusion Criteria • Patients not enrolled in the FORUM 2 platform trial (independently of the reason) • Patients ≥ 2 years of age at HSCT • Patients not in complete remission at the time of enrollment • Presence of transplant-associated thrombotic microangiopathy • Previous diagnosis of SOS/VOD not resolved since at least 3 weeks before study inclusion • Presence of idiopathic pneumonia syndrome • Ongoing immunosuppression for reasons other than standard GVHD prophylaxis • Patients who received TBI as part of their conditioning regimen or a chemotherapy-based conditioning regimen other than busulfan, thiotepa and fludarabine or treosulfan, thiotepa and fludarabine or busulfan and cyclophosphamide (±VP16). • Presence of active grade III-IV acute GVHD at the time of enrollment. • Presence of grade II acute GVHD with either gastrointestinal or liver involvement. • Clinically relevant active infections, including unresolved bacterial, fungal, or parasitic infections or active uncontrolled viral reactivations (e.g., CMV, EBV, or adenovirus). • ANC <0.5 × 109/L or self-sustained platelet count <30 x 109/L at time of study enrolment, • Creatinine clearance lower than 30 ml/min or serum bilirubin > 3 x ULN prior to start of treatment (unless related to Gilbert’s or Meulengracht disease). • Lansky performance status < 50. • Patients transplanted from related/unrelated CB.
6. O1 Sub-Study Exclusion Criteria • Patients not enrolled in the FORUM 2 platform trial (independently of the reason) • Patients <3 months or > 26 years of age at the time of informed consent.
7. O2 Sub-Study Exclusion Criteria • Patients not enrolled in the FORUM 2 platform trial (independently of the reason) • Patients <3 months or > 25 years of age at the time of informed consent. • Graft source represented by peripheral blood stem cells

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. R1 Sub-Study: The primary endpoint is Event Free Survival (EFS) at year 4. EFS is defined as the time from randomization (intention-to-treat analysis) or HSCT (per-protocol/as treated) to first failure event defined as follows: Failure events are: • Relapse • Death from any cause • Diagnosis of a second malignant neoplasm Patients without event will be censored at last follow-up date.
2. R2 Sub-Study: • Overall response rate (ORR) at Day 28 after randomization, defined as the proportion of patients in each arm demonstrating a complete response (CR) or partial response (PR) without requirement for additional systemic therapies for earlier progression, mixed response or nonresponse. Scoring of response will be relative to the organ stage at the time of randomization.
3. S1 Sub-Study: EFS is defined as the time from HSCT to first failure event defined as follows: Failure events are: - Relapse - Graft failure - Death from any cause - Diagnosis of a second malignant neoplasm Patients without event will be censored at last follow-up date.
4. P1 Sub-Study: Compare the CIR 2 years after HSCT in blinatumomab-treated patents and historical controls. CIR is calculated from the time of study enrolment until the date of relapse (defined as either bone marrow aspirate or biopsy with ≥ 5% blasts or as appearance of leukemia cells in an extramedullary site) or last follow-up (death from any cause other than leukemia relapse will be considered a competing event).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Comparator 1

Auxiliary 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ospedale Pediatrico Bambino Gesu

Sponsor organisation

Ospedale Pediatrico Bambino Gesu

Address

Piazza Di Sant'onofrio 4

City

Rome

Postcode

00165

Country

Italy

Scientific contact point

Organisation

Ospedale Pediatrico Bambino Gesu

Contact name

PROF FRANCO LOCATELLI

Public contact point

Organisation

Ospedale Pediatrico Bambino Gesu

Contact name

PROF FRANCO LOCATELLI

Third parties 1

Locations

9 EU/EEA countries · 64 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 245 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications