A Study of ARV-393 in Relapsed/Refractory Non-Hodgkin Lymphoma.

Official title

A Phase 1 First in Human Study of ARV-393 in Adult Participants With Advanced Non-Hodgkin's Lymphoma

Overview

This clinical trial is studying the safety and potential anti-tumor activity of an investigational drug called ARV-393 in patients diagnosed with advanced Relapsed/Refractory non-Hodgkin's lymphoma (R/R NHL) to determine if ARV-393 may be a possible treatment option. ARV-393 is thought to work by breaking down a protein present in many types of non-Hodgkins lymphomas, which may prevent, slow or stop tumor growth. This is the first time ARV-393 will be used by people. The investigational drug will be given as an oral tablet.

Detailed description

This is an open-label, global, multi-center monotherapy and combination dose escalation and dose optimization study to evaluate safety, tolerability and preliminary efficacy of ARV-393. The study will evaluate the safety and tolerability in ascending doses of ARV-393 as monotherapy (A) and in combination with glofitamab (C), as well as determine the RP2D in the dose optimization parts (B for monotherapy) and in combination with glofitamab (D for combination therapy). The monotherapy portions of the study will include participants with R/R NHL. The combination therapy portions of the study with glofitamab will include participants with R/R DLBCL.

Interventions

• Drug ARV-393
  Oral daily dose of ARV-393 at a specified dose level
• Drug Glofitamab
  Glofitamab infusion per labelled prescribing information

Primary outcome measures

• Incidence of Dose Limiting Toxicities During First 28 Days [Time frame: 28 days from first study dosing]
• Percentage of Participants With Adverse Events Characterized by Severity, Seriousness, and Relationship to Study Drug as a Measure of Safety and Tolerability [Time frame: Parts A and B: From the study baseline to 30 days after last dose of ARV-393; Parts C and D: From the study baseline to 40 days after last dose of ARV-393]
• Number of Participants With Abnormal Vital Signs, Abnormal ECG Readings (QT Interval) and Abnormal Laboratory Parameters [Time frame: Parts A and B: From the study baseline to 30 days after last dose of ARV-393; Parts C and D: From the study baseline to 40 days after last dose of ARV-393]
• Percentage of Participants With Grade 3 or Grade 4 Clinical Lab Abnormalities Using the Common Terminology Criteria for Adverse Events (CTCAE) With Scale From Grade 1 Grade 5. Higher Score Means Worse Outcome [Time frame: Parts A and B: From the study baseline to 30 days after last dose of ARV-393; Parts C and D: From the study baseline to 40 days after last dose of ARV-393]

Secondary outcome measures (10)

• Area Under the Curve to the End of the Dosing Period (Auctau) for ARV-393 [Time frame: 4 months from first drug dosing]
• Area Under the Concentration Versus Time Curve, from 0 To Last Measurable Concentration (AUC0-Last) for ARV-393 [Time frame: Time Frame: 4 months from first drug dosing]
• Maximum Concentration (Cmax) for ARV-393 [Time frame: 4 months from first drug dosing]
• Minimum Concentration (Cmin) for ARV-393 [Time frame: 4 months from first drug dosing]
• Time to Maximum Concentration (Tmax) for ARV-393 [Time frame: 4 months from first drug dosing]
• Oral Clearance (CL/F) for ARV-393 [Time frame: 4 months from first drug dosing]
• Volume of Distribution (Vd/F) for ARV-393 [Time frame: 4 months from first drug dosing]
• Overall Response Rate (ORR) Based on Investigator Assessments of Response According to Lugano Response Criteria for NHL and International Primary Central Nervous System Lymphoma (PCNSL) Criteria for Central Nervous System (CNS Lymphoma), if Applicable [Time frame: Approximately 2 years]
• Complete Response Rate (CRR) Based on Investigator Assessments of Response According to the Lugano Response Criteria for NHL and the International PCNSL Criteria for CNS Lymphoma, if Applicable [Time frame: Approximately 2 years]
• Duration of Response (DOR) Based on Investigator Assessments of Response According to the Lugano Response Criteria for NHL and the International PCNSL Criteria for CNS Lymphoma, if Applicable [Time frame: Approximately 2 years]

Eligibility criteria

Inclusion criteria

• For Part A and B: Have relapsed/refractory NHL and >=2 prior systemic therapies, (including rituximab), and be ineligible for known therapies with demonstrated clinical benefit per investigator assessment or, histologically confirmed AITL that has recurred or progressed following institutional standard of care therapy.
• For Part C and D: Have R/R DLBCL, not otherwise specified \[NOS (DLBCL, NOS)\] or large B-cell lymphoma (LBCL) arising from follicular lymphoma and have received two or more lines of systemic therapy.
• Have at least one bi dimensionally measurable lesion >1.5-centimeter (cm) in largest dimension for nodal or >1.0 cm for extranodal lesion.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 (NOTE: For Part A only - ECOG PS of 2 is allowed for participants with secondary CNS lymphoma).
• Adequate bone marrow function
• Adequate kidney function
• Adequate Liver Function

Exclusion criteria

• Current or past history of peripheral eosinophilia, hypereosinophilic syndrome (HES), organ-specific eosinophilic disorder, or drug reaction with eosinophilia and systemic symptoms (DRESS).
• Prior allogeneic stem cell transplant (SCT) or solid organ transplantation.
• Any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, melanoma in situ or carcinoma in situ of the breast or cervix, and prostate cancer with active surveillance.
• Any of the following in the previous 6 months:

• Myocardial infarction, long QT syndrome or family history of long QT syndrome, or Torsade de Pointes;
• Clinically important atrial or ventricular arrhythmias;
• Serious conduction system abnormalities, 3rd degree atrioventricular (AV block), unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (CHF), New York Heart Association Class III or IV;
• Cerebrovascular accident, transient ischemic attack, symptomatic pulmonary embolism, and/or other clinically significant episode of thromboembolic disease;
• Active inflammatory gastrointestinal (GI) disease, chronic diarrhea, previous gastric resection, or lap band surgery.
• Uncontrolled hypertension despite optimal medical treatment
• History of myocarditis.
• In ability to comply with listed prohibited treatments.
• Standard 12-lead electrocardiogram (ECG) that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results.
• Cardiac ejection fraction <45%.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 8 centers

• Clinical Trial Site — New Haven
• Clinical Trial Site — Detroit
• Clinical Trial Site — New Brunswick
• Clinical Trial Site — New York
• Clinical Trial Site — New York
• Clinical Trial Site — Cleveland
• Clinical Trial Site — Nashville
• Clinical Trial Site — Houston

Spain · 5 centers

• Clinical Trial Site — El Palmar
• Clinical Trial Site — Pamplona
• Clinical Trial Site — Barcelona
• Clinical Trial Site — Madrid
• Clinical Trial Site — Salamanca

Canada · 2 centers

• Clinical Trial Site — Toronto
• Clinical Trial Site — Montreal

Denmark · 2 centers

• Clinical Trial Site — Copenhagen
• Clinical Trial Site — Odense C

Identifiers

NCT: NCT06393738 · ARV-393-101 · 2023-510136-36-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗