IRB Study Number 24-055
Status Recruiting
Phase Phase 1
Institute Taussig Cancer Institute
Description
Primary Objectives
• To assess the safety and tolerability of NM32-2668
• To determine the maximum tolerated dose (MTD) sequence of NM32-2668
• To determine the Recommended Phase 2 Dose (RP2D) sequence(s) for NM32-2668
Secondary Objectives
• To characterize the pharmacokinetic (PK) profile of NM32-2668
• To evaluate the immunogenicity of NM32-2668 and its effects on relevant study outcomes
• To explore the preliminary anti-tumor activity of NM32-2668
Inclusion Criteria
Patients aged 18 years or older.
Patients who are able to understand and give written informed consent and comply with study procedures.
Patients with histologically confirmed, advanced-stage:
platinum-resistant serous, endometroid, clear-cell, or mucinous epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, or
serous, endometroid or clear-cell endometrial cancer, or
adenocarcinoma of the lung, or
triple-negative breast cancer, defined as negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), according to American Society of Clinical Oncology/College of American Pathologists recommendations (Hammond et al. 2010; Wolff et al. 2018), or
liposarcoma or leiomyosarcoma, or
malignant mesothelioma, or
gastric or gastroesophageal junction adenocarcinoma, or
malignant melanoma of the skin, or
clear-cell, papillary, or chromophobe renal cell carcinoma. Note: patients with mixed histology (e.g., present squamous component) may be eligible only if this accompanying histology is minimal and with prior written approval from the sponsor.
Confirmed ROR1 tumor expression (≥ 25% of tumor cells staining with ≥ 1+ intensity in Part I and ≥ 1% of tumor cells staining with ≥ 1+ staining intensity in Parts II and III), as assessed by a central laboratory using an investigational, analytically validated ROR1 assay. Participants without archival tumor tissue (less than 24 months old) available for testing must have a lesion amenable to biopsy. The requirement for ROR1 expression may be modified to include patients with higher ROR1 expression based on emerging data from the study. Patients with leiomyosarcoma or liposarcoma may be enrolled without prospective testing except in part I of the trial. 5. Patients who have undergone at least one prior systemic therapy and have radiologically or clinically determined progressive disease during or after most recent line of therapy, and for whom no further standard therapy is available, or who are intolerable or have medical contraindications to standard therapy.
Patients must have at least one measurable or non-measurable lesion as per RECIST version 1.1. Note: the measurable lesion(s) can be inside the field of prior radiotherapy provided that the lesion has documented progression post radiotherapy as per RECIST version 1.1.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Adequate organ function as defined by:
a. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L (1000 /μL) without administration of growth factors within past 14 days,
b. Platelets (PLT) ≥ 75.0 x 109/L (75 000/μL) without platelet transfusion within past 14 days,
c. Hemoglobin (HGB) ≥ 9.0 g/dL (patients may be transfused or have received erythropoietic support),
d. Creatinine clearance >50 mL/min using the Cockcroft-Gault formula,
e. Serum total bilirubin ≤ 1.5 x ULN (except patients with Gilbert’s syndrome, who must have total bilirubin ≤3.0 x ULN),
f. Aspartate aminotransferase (AST) ≤ 2.5 x ULN; alanine aminotransferase (ALT) ≤ 2.5 x ULN (AST, ALT ≤ 5 x ULN if present liver metastases),
g. International normalized ratio (INR) ≤ 1.5; activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN,
h. Q wave to T wave (QT) interval corrected for heart rate (QTc) ≤ 480 ms (Fridericia’s formula). Note: if laboratory results are outside the permitted range, the investigator may retest the patient and the subsequent within range screening result may be used to confirm eligibility.
Patients with no active bleeding.
Women of child-bearing potential (WOCBP), defined as a sexually mature woman who has not undergone surgical sterilization or who has not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months) must agree to use an effective contraceptive method (i.e., pregnancy rate of less than 1% per year); examples include oral, parenteral, or implantable hormonal contraceptive, intra-uterine device, barrier contraceptive with spermicide, partner’s latex condom or vasectomy) while on study treatment and for at least 90 days after the last dose of NM32-2668.
WOCBP must have a negative serum pregnancy test within 7 days prior to first dose of NM32-2668.
Male patients must agree to use a latex condom, even if they had a successful vasectomy, while on study treatment and for at least 90 days after the last dose of NM32-2668.
Male patients must agree not to donate sperm, and female patients must agree not to donate eggs, while on study treatment and for at least 90 days after the last dose of NM32-2668.
Exclusion Criteria
Prior treatment with any agent targeting ROR1 or prior treatment with a CD3 T-cell engaging therapy.
Prior treatment with chimeric antigen receptor (CAR) cell therapy within 90 days prior to first dose of NM32-2668.
Systemic anti-neoplastic therapy within five half-lives or 21 days, whichever is shorter, prior to first dose of NM32-2668. Note: investigational agents with half-life not determined may not be given within 21 days prior to first dose of NM32-2668. Note: patients receiving bisphosphonates or denosumab are not excluded.
Wide-field radiotherapy (> 30% of marrow-bearing bones) within 28 days, or focal radiation for analgesic purpose or for lytic lesions at risk of fracture within 14 days prior to first dose of NM32-2668, or no recovery from side effects of such prior interventions.
Major surgery (not including placement of vascular access device or tumor biopsies) within 28 days prior to first dose of NM32-2668, or no recovery from side effects of such prior intervention.
Symptomatic ascites or pleural effusions not yet addressed with adequate medical management.
Prior allogeneic bone marrow or solid organ transplantation.
Central nervous system (CNS) metastasis. Note: Patients with CNS metastasis are eligible if they were treated with surgical resection and/or radiotherapy for CNS metastasis at least 28 days prior first dose of NM32-2668 and meet all of the following criteria after the treatment: (1) no systemic steroid requirement, (2) neurological symptoms absent or stable, Grade ≤1, (3) follow-up magnetic resonance imaging (MRI) scan performed within 28 days prior to the first dose of NM32-2668 showing no progression of treated lesion(s) and no new lesion(s) appearing. Note: patients with history of leptomeningeal disease are excluded.
Persistent toxicities from previous systemic anti-neoplastic treatments of Grade >1 (or Grade >2, if baseline before administration of previous treatment was Grade 2). Note: patients with any grade alopecia, or Grade 2 of any of the following: sensory peripheral neuropathy, clinically stable diabetes mellitus, and hypothyroidism or adrenal insufficiency adequately treated with hormonal replacement are allowed. Note: laboratory parameters must follow values given in inclusion criterion No. 8.
Concurrent medical condition requiring the use of systemically active immunosuppressive medications, or patients having received treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids [doses >10 mg/day prednisone or equivalent], cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF alpha medications) within 2 weeks prior to initiation of NM32-2668 treatment, or anticipation of need for systemic immunosuppressive medication during NM32-2668 treatment, with the following exceptions:
a. Patients who receive acute, systemic immunosuppressant medication (e.g., single dose of dexamethasone for nausea/vomiting) may be enrolled in the study after discussion and confirmation by the sponsor;
b. Patients who receive short term (≤3 days) of systemic immunosuppressant medication, as long as not within 7 days prior to first administration of NM32-2668, may be enrolled in the study after discussion and confirmation by the sponsor;
c. Topical applications, eye drops, inhaled sprays or local injections of corticosteroids for conditions other than inclusion diagnosis are permitted;
d. The use of mineralocorticoids for management of orthostatic hypotension is permitted; and
e. The use of physiologic doses of corticosteroids for management of adrenal insufficiency is permitted. Note: systemic steroids for NM32-2668 premedication are allowed. Note: patients with pretreated CNS metastasis are not eligible if they require any dose of systemic steroids (except steroid premedication).
- Active autoimmune disease or a documented history of autoimmune disease that required systemic therapy within 2 years prior to Screening. Patients with documented history of autoimmune disease who required therapies other than dietary modification for disease control within 2 years prior to Screening must be discussed with the sponsor to determine eligibility status, except for the following cases, which are not exclusionary:
a. Patients with vitiligo, eczema, lichen simplex chronicus or psoriasis if the following conditions are met:
- Rash must cover ≤ 10% of body surface area; - Disease is well controlled at baseline and requires, at most, low-potency topical corticosteroids; and - No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.
b. Patients with Type I diabetes controlled with stable insulin therapy;
c. Patients who require intermittent use of bronchodilators, inhaled steroids, or local steroid injections including intra-articular injections; and
d. Patients on stable hormone replacement therapy (e.g., hypothyroidism treated with thyroid hormone).
History of thromboembolic events, including deep venous thrombosis or pulmonary emboli within the past 6 months prior to the administration of the first dose of NM32-2668. Note: patients with deep vein thrombosis or pulmonary embolism initially diagnosed within six months prior to first dose of NM32-2668 may be eligible if they are appropriately treated with anticoagulants (or are off anticoagulants if no longer indicated) and have no evidence of such disease at Screening.
Significant cardiac disease, such as recent (within six months prior to first dose of NM32-2668) myocardial infarction or acute coronary syndromes (including unstable angina pectoris), congestive heart failure (New York Heart Association class III or IV), uncontrolled hypertension, uncontrolled cardiac arrhythmias, severe aortic stenosis.
History of CNS disease such as hypertensive crisis/hypertensive encephalopathy, stroke, epilepsy, vasculitis, neurodegenerative disease within 12 months prior to the administration of the first dose of NM32-2668.
Acute and/or clinically significant bacterial, fungal or viral infection.
Known or suspected severe allergy/hypersensitivity (resulting in treatment discontinuation) to monoclonal antibodies or recombinant antibody-related fusion proteins.
Known or suspected intolerance, hypersensitivity reaction or idiosyncrasy to either of the components of NM32-2668 drug product or premedication medicines.
Concurrent participation in another investigational therapeutic clinical trial.
Pregnant or breast-feeding females.
Rapid disease progression, threat to vital organs or non-irradiated lesions ≥ 2 cm in diameter at critical sites (e.g., paraspinal, paratracheal) where tumor swelling may pose a threat to critical anatomical structures (e.g., CNS metastasis, respiratory failure due to tumor compression, spinal cord compression), and urgent alternative medical intervention is required.
Mental or medical conditions that prevent the patient from giving informed consent or participating in the trial, or other severe acute or chronic somatic or psychiatric conditions or laboratory abnormality that may increase the risk associated with the study participation or NM32-2668 administration or that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for enrollment in this study.
Prior history of malignancy other than inclusion diagnosis within five years prior to first dose of NM32-2668. Note: patients with adequately treated basal cell or squamous cell skin cancer, non-invasive superficial bladder cancer, in situ cervical cancer, in situ breast cancer, in situ prostate cancer may be eligible if they have shown no evidence of active disease for two years prior to first dose of NM32-2668.
