Study of PIT565 in Relapsed and/or Refractory B-cell Malignancies

• ClinicalTrials.gov Identifier: NCT05397496
• Recruitment Status: Recruiting
• First Posted: May 31, 2022
• Last Update Posted: February 27, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

This is an open-label, multicenter, phase I study, which primary objective is to characterize the safety and tolerability of PIT565 and to identify maximal tolerated doses (MTDs) and/or recommended doses (RDs), schedule and route of administration in relapsed and/or refractory B-cell Non-Hodgkin lymphoma (R/R B-NHL) and relapsed and/or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL).

Condition or disease	Intervention/treatment	Phase
B-cell Non-Hodgkin Lymphoma (B-NHL); B-cell Acute Lymphoblastic Leukemia (B-ALL)	Biological: PIT565	Phase 1

Detailed Description:

This is an open-label, multicenter, phase I study of PIT565 in patients with R/R B-NHL and R/R B-ALL.

The study comprises a dose escalation part of PIT565 in two independent groups (group A: R/R B-NHL and B: R/R B-ALL) and a dose expansion part in three independent groups (relapsed and/or refractory large B-cell lymphoma (R/R LBCL) who received CAR-T therapy (A2) or not (A1), and R/R B-ALL (B1)).

During the dose escalation, the safety (including the dose-dose limiting toxicity (DLT) relationship) and tolerability of PIT565 will be assessed, and schedule(s), route(s) of administration and dose(s) will be identified for use in the expansion part based on the review of these data. The recommended dose (RD) will also be guided by the available information on pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity. The dose escalation will be guided by an adaptive Bayesian logistic regression model (BLRM) following the Escalation with Overdose Control (EWOC) principle.

Different schedules (once weekly (Q1W) or once every 2 weeks (Q2W) with and without priming dose) and routes of administrations (intravenous (i.v.) or subcutaneous (s.c.)) will be explored in the dose escalation groups.

The dose expansion will further explore the MTD(s) and/or RD(s) and the selected schedule(s) and route of administration(s) in the three patients' groups.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 140 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I, Open-label, Multi-center Study of PIT565 in Patients With Relapsed and/or Refractory B-cell Malignancies
• Actual Study Start Date: October 3, 2022
• Estimated Primary Completion Date: February 28, 2025
• Estimated Study Completion Date: February 27, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: PIT565 Group A (dose escalation part); PIT565 in adult NHL patients for whom two or more lines of chemotherapy have failed and either having progressed (or relapsed) after autologous hematopoietic stem cell transplantation (HSCT), or being ineligible for or not consenting to the procedure	Biological: PIT565; Intravenous (i.v.) infusion or Subcutaneous (s.c.) injection
Experimental: PIT565 Group B (dose escalation part); PIT565 in adult R/R ALL patients	Biological: PIT565; Intravenous (i.v.) infusion or Subcutaneous (s.c.) injection
Experimental: PIT565 Group A1 (dose expansion part); PIT565 in adult R/R large B-cell lymphoma (LBCL) (DLBCL, double/triple hit High-grade B-cell lymphoma (HGBCL), Primary mediastinal large B-cell lymphoma (PMBCL), Follicular lymphoma grade 3B (FL3B)) patients who did not receive CD19-directed CAR-T therapy	Biological: PIT565; Intravenous (i.v.) infusion or Subcutaneous (s.c.) injection
Experimental: PIT565 Group A2 (dose expansion part); PIT565 in adult R/R LBCL (DLBCL, double/triple hit HGBCL, PMBCL, FL3B) patients who received CD19-directed CAR-T therapy	Biological: PIT565; Intravenous (i.v.) infusion or Subcutaneous (s.c.) injection
Experimental: PIT565 Group B1 (dose expansion part); PIT565 in adult R/R ALL patients	Biological: PIT565; Intravenous (i.v.) infusion or Subcutaneous (s.c.) injection

Outcome Measures

Primary Outcome Measures :

1. Incidence and severity of Dose Limiting Toxicities (DLTs) [ Time Frame: 28 days or 35 days, depending on the dosing schedule ]
   Assessment of safety of study drug. A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value of CTCAE grade 3 or higher that occurs within the DLT evaluation period (28 days or 35 days depending on the schedule) and that is not primarily related to disease, disease progression, intercurrent illness, or concomitant medications with exceptions provided in the clinical protocol.
2. Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: 21 months ]
   Assessment of safety of study drug.
3. Frequency of dose interruptions [ Time Frame: 21 months ]
   Assessment of tolerability of study drug
4. Frequency of dose reductions [ Time Frame: 21 months ]
   Assessment of tolerability of study drug
5. Dose intensities [ Time Frame: 21 months ]
   Assessment of tolerability of study drug Dose intensity is defined as the ratio of actual cumulative dose received and actual duration of exposure.

Secondary Outcome Measures :

1. Overall Response Rate (ORR) [ Time Frame: 21 months ]
   Evaluation of anti-tumor activity of PIT565 for Non-Hodgkin Lymphoma will be based on the Lugano Response Criteria Classification and anti-tumor activity of PIT565 for Acute Lymphoblastic Leukemia will be based on National Comprehensive Cancer Network (NCCN) 2018 v1 guidelines. Local investigator assessment will be used for analysis of efficacy endpoints.
2. Complete Response (CR) rate [ Time Frame: 21 months ]
   Evaluation of anti-tumor activity of PIT565 for Non-Hodgkin Lymphoma will be based on the Lugano Response Criteria Classification and anti-tumor activity of PIT565 for Acute Lymphoblastic Leukemia will be based on National Comprehensive Cancer Network (NCCN) 2018 v1 guidelines. Local investigator assessment will be used for analysis of efficacy endpoints.
3. Best Overall Response (BOR) [ Time Frame: 21 months ]
   Evaluation of anti-tumor activity of PIT565 for Non-Hodgkin Lymphoma will be based on the Lugano Response Criteria Classification and anti-tumor activity of PIT565 for Acute Lymphoblastic Leukemia will be based on National Comprehensive Cancer Network (NCCN) 2018 v1 guidelines. Local investigator assessment will be used for analysis of efficacy endpoints.
4. Duration Of Response (DOR) [ Time Frame: 21 months ]
   Evaluation of anti-tumor activity of PIT565 for Non-Hodgkin Lymphoma will be based on the Lugano Response Criteria Classification and anti-tumor activity of PIT565 for Acute Lymphoblastic Leukemia will be based on National Comprehensive Cancer Network (NCCN) 2018 v1 guidelines. Local investigator assessment will be used for analysis of efficacy endpoints.
5. Overall Survival (OS) [ Time Frame: 33 months ]
   Evaluation of anti-tumor activity of PIT565 for Non-Hodgkin Lymphoma will be based on the Lugano Response Criteria Classification and anti-tumor activity of PIT565 for Acute Lymphoblastic Leukemia will be based on National Comprehensive Cancer Network (NCCN) 2018 v1 guidelines. Local investigator assessment will be used for analysis of efficacy endpoints.
6. Progression Free Survival (PFS) [ Time Frame: 21 months ]
   Evaluation of anti-tumor activity of PIT565 for Non-Hodgkin Lymphoma will be based on the Lugano Response Criteria Classification Local investigator assessment will be used for analysis of efficacy endpoints.
7. Event-free survival (EFS) [ Time Frame: 21 months ]
   Evaluation of anti-tumor activity of PIT565 for Acute Lymphoblastic Leukemia will be based on National Comprehensive Cancer Network (NCCN) 2018 v1 guidelines. Local investigator assessment will be used for analysis of efficacy endpoints.
8. Maximum concentration of PIT565 (Cmax) [ Time Frame: 21 months ]
   Pharmacokinetics (PK) parameters will be determined using non-compartmental method(s)
9. Area Under the Curve of PIT565 (AUC) [ Time Frame: 21 months ]
   Pharmacokinetics (PK) parameters will be determined using non-compartmental method(s)
10. Trough concentration of PIT565 (C trough) [ Time Frame: 21 months ]
    Pharmacokinetics (PK) parameters will be determined using non-compartmental method(s)
11. Prevalence of Anti-drug antibodies (ADA) at baseline [ Time Frame: Baseline ]
    Assessment of anti-PIT565 antibodies in serum.
12. Incidence of Anti-drug antibodies (ADA) on treatment [ Time Frame: 21 months ]
    Assessment of anti-PIT565 antibodies in serum.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Signed informed consent must be obtained prior to participation in the study.
• Male or female patients ≥18 years of age at the date of signing the informed consent form
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2

NHL patient population

• Refractory or relapsed B-NHL
• Must have relapsed after or failed to respond to at least two prior treatment therapies including an αCD20 monoclonal antibody containing chemotherapy combination regimen
• Must have at least one bi-dimensionally measurable nodal lesion or one bi-dimensionally measurable extranodal lesion, as measured on positron emission tomography-computed tomography (PET/CT) scan

ALL patient population

• Refractory or relapsed CD19-positive B-ALL
• Morphologic disease in the bone marrow (≥ 5% blasts)

Exclusion Criteria:

• History of severe hypersensitivity to any ingredient of the study treatment or its excipients
• Contraindication to tocilizumab
• History of ongoing, chronic or recurrent infectious disease, or evidence of tuberculosis infection
• Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers, and completely resected carcinoma in situ of any type
• Active central nervous system (CNS) involvement by malignancy or presence of symptomatic CNS metastases, or CNS metastases that require local CNS-directed therapy (such as radiotherapy or surgery), or increasing doses of corticosteroids within the 2 weeks prior to the start of study treatment
• Active, known or suspected autoimmune disease other than patients with vitiligo, residual hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment or conditions not expected to recur
• Patients receiving systemic treatment with any immunosuppressive medication (other than steroids as described above)

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Contacts

Contact: Novartis Pharmaceuticals; 1-888-669-6682; novartis.email@novartis.com

Contact: Novartis Pharmaceuticals; +41613241111; novartis.email@novartis.com

Locations

France

Novartis Investigative Site; Recruiting

Marseille, France, 13273

Israel

Novartis Investigative Site; Recruiting

Tel Aviv, Israel

Italy

Novartis Investigative Site; Recruiting

Milano, MI, Italy, 20133

Japan

Novartis Investigative Site; Recruiting

Kashiwa, Chiba, Japan, 277 8577

Spain

Novartis Investigative Site; Recruiting

Barcelona, Catalunya, Spain, 08035

Sponsors and Collaborators

Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT05397496
• Other Study ID Numbers: CPIT565A12101; 2022-000367-45 ( EudraCT Number )
• First Posted: May 31, 2022
• Last Update Posted: February 27, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Phase I; Trispecific antibody; Non-Hodgkin lymphoma; Acute Lymphoblastic Leukemia; PIT565

Additional relevant MeSH terms:

Lymphoma, Non-Hodgkin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Lymphoma, B-Cell; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia