A Ph2 Superiority Study with InO Monotherapy vs ALLR3 for Induction Treatment of Childhood HR ALL

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pfizer Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

13 May 2023 → ongoing

Decision date (initial)

2024-09-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Pfizer Inc., 66 Hudson Boulevard East, New York, NY 10001, USA

External identifiers

EU CT number

2023-509810-13-00

EudraCT number

2022-000186-40

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Safety, Therapy, Pharmacokinetic, Pharmacogenomic

To demonstrate the superiority of Inotuzumab Ozogamicin (InO) monotherapy vs ALLR3 induction in paediatric participants between 1 and less than 18 years with HR first bone marrow relapse CD22-positive B-cell precursor acute lymphoblastic leukaemia (BCP ALL.)

Secondary objectives 4

1. To evaluate the long-term efficacy of InO monotherapy vs ALLR3 regimen with respect to event-free survival (EFS).
2. To evaluate the long-term efficacy of InO monotherapy vs ALLR3 regimen with respect to: • Duration of response (DOR) • Hematopoietic stem cell transplant (HSCT) rate • Chimeric antigen receptor (CAR) T-cell therapy rate • Overall survival (OS)
3. To evaluate the safety and tolerability of InO monotherapy vs ALLR3 induction
4. To evaluate the pharmacokinetics (PK) of InO

Conditions and MedDRA coding

Acute Lymphoblastic Leukemia (ALL)

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-001429-PIP01-13

Plan to share IPD

Yes

IPD plan description

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Male or female participants between 1 and less than 18 years of age.
2. Type of Participant and Disease Characteristics: Morphologically confirmed diagnosis of first relapse HR BCP ALL; HR first relapse is defined as relapse occurring within 18 to 30 months of original diagnosis of ALL or within 6 months of completion of primary therapy, and lacking any identified very high risk genetic abnormalities • CD22-positive ALL as defined by local institution; • Bone marrow involvement of ≥ 5% leukemic blasts (≥ M2 status).
3. Other Inclusion Criteria: Adequate serum chemistry parameters: • An estimated glomerular filtration rate (eGFR) in participants 1 to less than 2 years of age, or estimated creatinine clearance (eCrCl) in those 2 to less than 18 years of age, ≥30 mL/min using the recommended formula • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 × institutional ULN at the time of randomization or precytoreduction/ general anesthesia; • Total bilirubin ≤1.5 × institutional ULN unless the participant has documented Gilbert's syndrome;
4. Prior history of thrombosis during corticosteroid use and/or asparaginase are eligible provided the participant receives anticoagulant prophylaxis per institutional guidelines.
5. Cardiac shortening fraction ≥ 30% by echocardiogram or ejection fraction > 50% by MUGA.

Exclusion criteria 6

1. Any history of: • Prior or ongoing hepatic SOS or prior liver failure [defined as severe acute liver injury with encephalopathy and impaired synthetic function (INR of ≥1.5)]; • Prior allo-HSCT or CAR T-cell therapy; • Isolated extramedullary leukemia; • Philadelphia-chromosome positive ALL, ie. BCR-ABL/t(9;22) present; • Presence of Grade 3 or Grade 4 peripheral neuropathy as defined in the Delphi consensus of acute toxic effects for childhood ALL; • Hypersensitivity to the active ingredient of InO or any of its excipients; • Hypersensitivity/allergy to both PEG-ASP and Erwinia-ASP; • Intolerance to any of the ALLR3 agents (mitoxantrone, vincristine, dexamethasone, asparaginase); • Grade 3 or Grade 4 pancreatitis due to any cause, as defined by CTCAE v4.03; • Grade 3 or Grade 4 allergic reaction to a monoclonal antibody; • Participants not fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy, defined as resolution of all such non-hematologic toxicities to Grade ≤2 per the NCI CTCAE v 4.03 prior to randomization, with the exception of the laboratory abnormalities as defined by other inclusion/exclusion criteria; • Down syndrome; • Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study; • Charcot-Marie-Tooth disease.
2. Prior/Concomitant Therapy with: • A calicheamicin-conjugated antibody (eg, InO or gemtuzumab ozogamicin) or prior therapy with a CD22 targeted therapy (immunotoxin or CAR T-cell therapy); • Cytotoxic therapy within 7 days prior to enrollment, with the exception of hydroxyurea and corticosteroids which are permitted prior to initiating study intervention. Participants may have receivedintrathecal chemotherapy at any time prior to study entry. NOTE: No waiting period is required for participants who relapse while receiving first-line maintenance chemotherapy. • Any radiation therapy within 28 days prior to enrollment; • The last dose of granulocyte stimulating factor (ie, Neupogen or equivalent) administered within 7 days prior to study enrollment and the last dose of pegfilgrastim (Neulasta®) given within 14 days prior to enrollment; • Less than 3 half-lives elapsed after the last dose of a mAb (eg, rituximab=66 days, epratuzumab=69 days). Participants must not have received blinatumomab within 4 weeks before study enrollment; • Current use of any prohibited concomitant medication(s) or participants unwilling/unable to use a permitted concomitant medication(s); • Any vaccination with live viral vaccines within 2 weeks of the start of study therapy. Prior/Concurrent Clinical Study Experience:
3. Administration of an IP (eg, drug or vaccine) concurrent with study intervention or within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer). A participant may be eligible if they are in the follow-up phase of an investigational study if they meet the criterion for time elapsed from previous administration of IP. Cases must be discussed with sponsor's medical monitor to judge eligibility.
4. Diagnostic Assessments: Serum or urine pregnancy test positive at screening.
5. Baseline 12 lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (eg, QTcF interval >470 msec, complete LBBB, signs of an acute or indeterminate age myocardial infarction, STT interval changes suggestive of myocardial ischemia, second or third degree AV block, or serious bradyarrhythmias or tachyarrhythmias). If QTcF >470 msec, the ECG should be repeated 2 more times the average of the 3 QTcF values should be used to determine the participant's eligibility. Computer interpreted ECGs should be over read locally by a physician experienced in reading ECGs before excluding participants.
6. Participants with active infection, including (but not limited to) HBV, HCV, and known HIV or AIDS-related illness. • HIV infection with CD4+ count <200/mm3 and viral load of >400 copies/mm3. Participants with stable well-controlled HIV infection may be eligible after consultation with the sponsor. HBV • Participants with a positive HBsAg (ie, either acute or chronic active hepatitis) are excluded. • Participants with HBV antibody positivity indicating immunity, either due to vaccination or prior natural infection, are eligible. •Participants with positive anti-HBcAb but negative HBsAg and anti- HBsAb profile, depending on clinical circumstances, may be eligible. Discussion with the sponsor is indicated. HCV • Participants with active HCV as determined by viral load.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Minimal residual disease (MRD)-negative, CR/CRp/CRi (per investigator assessment) at the end of induction therapy (MRD negativity is assessed by central lab and defined as leukemic blasts <1x10-4 by real time quantitative polymerase chain reaction (RQ-PCR) [with reflex to FC result if MRD is non-evaluable by RQ-PCR]).

Secondary endpoints 6

1. EFS, defined as the time from randomization until objective progression, relapse from CR/CRp/CRi, based on investigator assessment per response criteria, failure to achieve CR/CRp/CRi by the end of induction, MRD persistence prior to HSCT, second malignancy, or death due to any cause.
2. DOR, defined as time from date of first documented response (CR/CRp/CRi) to the date of first documented objective progression, relapse from CR/CRp/CRi as determined by investigator assessment per modified NCCN response criteria, MRD persistence prior to HSCT, or death due to any cause, whichever occurs first.
3. HSCT (and CAR T-cell therapy) rate, defined as the number and percentage of participants being transplanted and those receiving CAR Tcell therapy after treatment with InO or ALLR3.
4. OS, defined as the time from the date of randomization to the date of death due to any cause.
5. Incidence and severity of AEs graded per NCI CTCAE v4.03.
6. Cmax and Ctrough

Investigational products

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

Test 1

Comparator 8

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pfizer Inc.

Sponsor organisation

Pfizer Inc.

Address

66 Hudson Boulevard East

City

New York

Postcode

10001-2189

Country

United States

Scientific contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Public contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Third parties 4

Locations

16 EU/EEA countries · 65 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Corrective measures 1 · Art. 77 CTR

Results and documents

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

Documents 166 files

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

Application history

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