IRB Study Number 24-817
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
• To evaluate the safety and tolerability of ARV-393, determine MTD if necessary, and identify the RP2D(s) and dosing schedule
Secondary Objectives
• To characterize the pharmacokinetic profile of ARV-393 in plasma
• To assess the preliminary anti-tumor activity of ARV-393
Inclusion Criteria
Informed Consent:
- Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Age and Sex:
Participant must be male or female ≥18 years of age, inclusive, at the time of signing the informed consent. Written informed consent must be obtained prior to the initiation of study procedures.
Male participants or female participants of childbearing potential must agree to the contraception criteria outlined in Appendix 4 for male participants (Section 10.4.1) and female participants (Section 10.4.2), during treatment until 90 days and 180 days after the last dose of study intervention, respectively
Male participants must agree to refrain from donating sperm during treatment until 90 days after the last dose of study intervention, as per Appendix 4. Female participants must agree to refrain from donating eggs during treatment until 180 days after the last dose of study intervention, as per Appendix 4.
Type of Participant and Disease Characteristics:
- Diagnosis of one of the following (participants must have relapsed or refractory disease or be intolerant to the immediate prior therapy and have no available standard of care therapy):
• Pathological confirmed diagnosis of relapsed/refractory mature B-cell NHL according to The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee (Campo et al. 2022) (excluding hairy cell leukemia, lymphoplasmacytic lymphoma, IgM monoclonal gammopathy of undetermined significance, primary cold agglutin disease, heavy chain diseases, plasma cell neoplasms, monoclonal Ig deposition diseases, B -cell prolymphocytic leukemia, pediatric type follicular lymphoma, and primary DLBCL of the CNS).
o Participants should have relapsed/refractory disease, have received at least 2 prior systemic therapies, and be ineligible for known therapies with demonstrated clinical benefit. OR
• AITL: relapsed/refractory histologically proven nTFHL-AI that has recurred or progressed following institutional standard of care therapy and must have received at least one prior line of therapy.
Must have at least one bi-dimensionally measurable lesion >1.5 cm in largest dimension for nodal or >1.0 cm for extranodal lesion.
Histopathology report must be available as source documentation. Participants with transformed follicular lymphoma or Richter’s transformation are included. Pathology reports at the time of disease transformation must be provided. The results of tests conducted on the tissue at diagnosis (eg, cell of origin), other abnormalities (eg, BCL2, BCL6, and MYC abnormalities) should be provided if available.
Confirmed availability of archival or freshly biopsied tumor tissue prior to study enrollment. If archival tissue not available and fresh biopsy not feasible due to inaccessibility of the tumor or safety considerations based on investigator assessment, the participant may be eligible for enrollment; contact the Study Medical Monitor.
Weight: ≥40 kg.
Other Inclusion Criteria:
ECOG PS 0 or 1.
Adequate bone marrow function defined as:
• ANC ≥1,000/mm3 or 1.0×109/L; growth factor support allowed in case of bone marrow involvement with lymphoma; and
• Platelets ≥75,000/mm3 or 75×109/L without transfusion support within 14 days prior to first dose of ARV-393; and
• Hemoglobin ≥9 g/dL without transfusion support within 7 days prior to first dose of ARV-393.
Estimated glomerular filtration rate ≥60 mL/min based on the MDRD study equation within 14 days prior to and including C1D1
Adequate Liver Function, defined as:
• Tbili ≤1.5×ULN unless the participant has documented Gilbert’s syndrome;
• AST and ALT ≤2.5×ULN, unless participant has liver involvement due to lymphoma in which case AST and ALT ≤5×ULN;
• ALP ≤2.5×ULN.
• PT, INR, aPTT ≤1.5×ULN. Participants on stable anticoagulant dose are permitted to enroll
- Resolution of acute side effects of any prior therapy to either baseline severity or CTCAE Grade ≤1 (except for alopecia, Grade ≤2 peripheral neuropathy)
Exclusion Criteria
Medical Conditions:
Active CNS involvement including leptomeningeal disease at the time of study enrollment.
Current or past history of peripheral eosinophilia, HES, organ-specific eosinophilic disorder, DRESS
Autologous SCT within 100 days prior to C1D1.
Prior allogeneic SCT or solid organ transplantation.
Prior treatment with CAR T-cell therapy within 60 days prior to C1D1.
Treatment emergent immune related AEs ≥Grade 3 that did not resolve to ≤Grade 1 or baseline associated with prior immunotherapeutic agents (eg, checkpoint inhibitors) or CAR-T therapy. If participant had immune related Grade ≥3 events, discuss case with Study Medical Monitor. Participants with stable immune related toxicity such as hypothyroidism on HRT, adrenal insufficiency on <10 mg prednisone or equivalent are permitted to enroll.
Medical condition that requires systemic steroid therapy (prednisone ≥10 mg/day or equivalent, except in the case of immune related adrenal insufficiency from prior checkpoint inhibitor therapy) or requirement for other immunosuppressive therapy. Inhaled steroids or topical steroids are permitted.
Participants with 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, Bowen’s disease, prostate intraepithelial neoplasm or ≤6 Gleason grade prostate cancer.
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 (including sustained ventricular tachyarrhythmia and ventricular fibrillation)
• Serious conduction system abnormalities (eg, bifascicular block [defined as right bundle branch and left anterior or posterior hemiblock], 3rd degree AV block), unstable angina, coronary/peripheral artery bypass graft, symptomatic CHF, New York Heart Association class III or IV,
• Cerebrovascular accident, transient ischemic attack, symptomatic pulmonary embolism, and/or other clinically significant episode of thrombo-embolic disease.
• If a participant has a cardiac rhythm device/pacemaker placed and QTcF >470 msec, the participant may be considered eligible. Participants with cardiac rhythm device/pacemaker must be discussed in detail with the Study Medical Monitor to assess eligibility.
Active inflammatory GI disease, chronic diarrhea, previous gastric resection, or lap band surgery. Gastroesophageal reflux disease under treatment with proton pump inhibitors is allowed (assuming no drug interaction potential).
Clinically active interstitial lung disease or pneumonitis, history of interstitial lung disease or (non-infectious) pneumonitis that required steroid treatment, idiopathic pulmonary fibrosis, drug induced pneumonitis, pulmonary disease requiring supplemental oxygen, poorly controlled asthma or COPD.
Clinically important (eg, uncontrolled) hypertension (>160/90 mm Hg) despite optimal medical therapy. BP should be ≤160/90 mm Hg prior to first dose of ARV-393.
Known or suspected hypersensitivity to ARV-393 or any of its excipients.
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.
History of myocarditis.
Prior/Concomitant Therapy:
Current use of any prohibited concomitant medication(s) which cannot be discontinued at least 14 days prior to the start of study intervention and for the duration of the study, or those who are unwilling/unable to follow the requirement for prohibited concomitant medication(s). See Section 6.9.
Participants on stable anticoagulant dose are permitted to enroll eg, prophylactic anticoagulation for atrial fibrillation, prophylactic anticoagulation for DVT. Refer to anticoagulation treatment in accordance with ASCO guidelines especially use of LMWH (Key et al. 2019; 2023). Use of direct anticoagulants is permitted provided consideration is given to any potential DDIs (see Appendix 5).
Systemic anti-cancer therapy (except hormonal therapy for maintenance treatment of breast or prostate cancer) within 28 days or 5 half-lives of the drug prior to administration of study intervention (whichever is shorter).
Treatment with radiotherapy within 2 weeks prior to first administration of study intervention. If participants have received radiotherapy within 4 weeks prior to first administration of study intervention, they must have at least one measurable lesion outside the radiation field. Participants who have only one measurable lesion that was previously irradiated but has progressed subsequently are eligible.
Participants sustaining major surgery defined as a complex procedure performed under regional or general anesthesia with a recovery period of <4 weeks prior to study enrollment.
Prior/Concurrent Clinical Study Experience:
- Participation in other studies involving investigational drug(s) within 28 days or 5 half-lives of the prior investigational therapy (whichever is longer) prior to study entry. A participant may be eligible even if they are in the follow-up phase of an investigational study as long as they haven’t received treatment in the study for at least 28 days (or 5 half-lives as noted above). Case must be discussed with the Study Medical Monitor to judge eligibility.
Diagnostic Assessments:
Serum pregnancy test (for females of childbearing potential) positive at screening
Active, uncontrolled bacterial, fungal, or viral infection requiring systemic antimicrobial therapy, including HBV, HCV, known HIV, or AIDS-related illness.
• In equivocal cases, participants whose viral load is negative, are eligible.
• The HIV-seropositive participants who are healthy and low risk for AIDS related outcomes could be considered eligible. HIV positive participants should have an undetectable viral load.
Participants with a known positive SARS-CoV-2 infection, regardless of improving symptoms.
Baseline (screening) standard 12-lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results:
• For example, baseline QTcF >470 msec, complete left bundle branch block, signs of an acute or indeterminate age myocardial infarction, STT interval changes suggestive of active myocardial ischemia, second- or third-degree AV block, or serious bradyarrhythmias or tachyarrhythmias).
• If the baseline uncorrected QT is >470 msec, this interval should be rate corrected using the Fridericia method and the resulting QTcF should be used for decision making and reporting.
• The average of the 3 QTcF or QRS complex values should be used to determine the participant’s eligibility. Computer interpreted ECGs should be over-read by a physician experienced in reading ECGs before excluding participants. Cases must be discussed in detail with the Study Medical Monitor to assess eligibility.
Cardiac ejection fraction <45% based on ECHO or MUGA scan.
Contraindication to uric acid lowering agents.
Other Exclusions:
Investigator site staff or Sponsor employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members.
Female participant is pregnant, planning to become pregnant during the study conduct, or breast feeding.
