A Phase 1 of CTX-8371 in Patients With Advanced Malignancies

Study Overview
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Brief Summary
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This is a Phase 1, open-label, first-in-human study of CTX-8371 administered as a monotherapy in patients with metastatic or locally advanced malignancies. The study will be conducted in 2 cohorts: Dose Escalation and Dose Expansion.

Detailed Description
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This Phase 1, open-label, first-in-human study will evaluate the safety, tolerability, immunogenicity, and pharmacokinetic profile of CTX-8371 monotherapy. Preliminary anti-tumor activity of CTX-8371 will also be assessed. The study will be conducted in 2 cohorts: Dose escalation and Dose expansion. The Dose Escalation Cohort will utilize a 3+3 design to evaluate five dose levels (0.1-10 mg/kg) of CTX-8371 given as an IV infusion once every 2 weeks. Patients in the Dose Expansion Cohort will receive CTX-8371 as an IV infusion at a dose(s) based on data from the Dose Escalation Cohort.

Official Title
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A Phase 1, Open-Label, Multiple-Ascending Dose Study of the Safety and Tolerability of CTX-8371 in Patients With Advanced Malignancies

Conditions
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Non Small Cell Lung Cancer, Triple Negative Breast Cancer, Hodgkin Lymphoma, Head and Neck Squamous Cell Carcinoma, Malignant Melanoma

Intervention / Treatment
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* Drug: CTX-8371


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older Patients must have a histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic disease that is relapsed/refractory to standard therapy or for which no effective standard therapy is available, including Malignant Melanoma (MM) Patients who have progressed after a minimum of 2 doses of a PD-1/PD-L1 treatment. Study enrollment (C1D1) must be within 6 weeks of the last dose of the anti-PD-1/PD-L1 blocking antibody. Patients must have had prior testing for BRAF V600 mutations.- Patients with BRAF V600 activating mutation must have received prior therapy with a BRAF/MEK inhibitor. Uveal and mucosal melanoma are excluded. Head and Neck squamous cell carcinoma (HNSCC) HNSCC of oral cavity, oropharynx, hypopharynx, or larynx Patients who have progressed after a minimum of 2 doses of a PD-1/PD-L1 treatment. Study enrollment (C1D1) must be within 6 weeks of the last dose of the anti-PD-1/PD-L1 blocking antibody. Patients must have received prior treatment with platinum-based chemotherapy. Non-Small Cell Lung Cancer (NSCLC) Patients who have progressed after a minimum of 2 doses of a PD-1/PD-L1 treatment. Study enrollment (C1D1) must be within 6 weeks of the last dose of the anti-PD-1/PD-L1 blocking antibody. Patients must have received prior treatment with platinum-based chemotherapy. Triple Negative Breast Cancer (TNBC) ER/PR and HER2 status should be defined by ASCO/CAP guidelines (JCO Allison et al 2020). Patients with HER2-low cancers (IHC 1+ or FISH-negative) are excluded. Patients must have received prior sacituzumab govitecan and if PD-L1 ≥10% by CPS pembrolizumab with chemotherapy. Classical Hodgkin Lymphoma (HL) Patients must have received at least two prior systemic therapies including brentuximab vedotin (if eligible) and a prior PD-1 inhibitor Patients must have experienced less than a CR (according to Lugano criteria to anti- PD-1 treatment Patients with NSCLC, MM, TNBC, and HNSCC must have measurable disease per RECIST 1.1. Patients with HL must have at least one measurable lesion > 1.5 cm for nodal, > 1.0 cm for extranodal FDG-avid disease by the Lugano (2014) response criteria. Tumor sites that are considered measurable must not have received prior radiation Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Adequate bone marrow function defined by absolute neutrophil (ANC) of ≥ 1.5×109/L, platelet count of ≥ 100.0×109/L, and hemoglobin of ≥ 9.0 g/dL (with or without transfusion) Adequate hepatic function defined as serum total bilirubin ≤ 1.5 × ULN, AST/ALT ≤ 2.5 × ULN (or ≤ 5 × ULN in patients with liver metastases) Adequate renal function defined as creatinine clearance ≥ 30mL/min by Cockcroft-Gault equation Female patients must be surgically sterile (or have a monogamous partner who is surgically sterile) or be at least 2 years postmenopausal or commits to use 2 acceptable forms of birth control (defined as the use of an intrauterine device (IUD), a barrier method with spermicide, condoms, any form of hormonal contraceptives) or abstinence for the duration of the study and for 4 months following the last dose of study treatment. Male patients must be sterile (biologically or surgically) or commit to the use of a reliable method of birth control (condoms with spermicide) for the duration of the study and for 4 months following the last dose of study treatment. Female patients who are women of childbearing potential (WOCBP) must have a negative serum pregnancy test at Screening within 7 days of dosing with CTX-8371 Last dose of previous PD-1 or PD-L1 therapy ≥ 28 days, other anticancer therapy > 21 days (or 2 half-lives for proteins, whichever is longer), radiotherapy >21 days (concurrent localized palliative radiotherapy is allowed during CTX-8371 treatment), or surgical intervention >21 days prior to the first dose of CTX-8371 Resolution of all prior anti-cancer therapy toxicities ≤ Grade 2 Capable of understanding and complying with protocol requirements Signed and dated institutional review board (IRB)/independent ethics committee (IEC)-approved informed consent form (ICF) before any protocol-directed screening procedures are performed Exclusion Criteria: Developed clinically significant adverse reaction to PD-1 or PD-L1 therapy, including immune related adverse reactions, which led to discontinuation of treatment Systemic therapy with immunosuppressive agents within 7 days before the start of CTX-8371 treatment. Topical, intranasal, intraocular, or inhaled corticosteroids and physiologic replacement for patients with adrenal insufficiency are allowed Patient is a pregnant or lactating WOCBP Prior organ transplantation Patients with evidence of active hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV) infection. Patients with positive HBsAg and/or detectable HBV DNA are eligible only if adequately controlled on antiviral therapy according to institutional standards and liver function eligibility criteria are also met. HCV patients showing sustained viral response or patients with immunity to HBV infection may enroll. Active autoimmune disease or medical conditions requiring chronic steroid (i.e., > 10 mg/day prednisone or equivalent) or immunosuppressive therapy. Patients with a prior history of autoimmune disease may be eligible following discussion with the Medical Monitor Other medical condition that in the opinion of the Investigator and/or Sponsor Medical Monitor may interfere with the conduct and/or interpretation of the current study, including: Congestive heart failure (> New York Heart Association Class II), active coronary artery disease, unevaluated new onset angina within 3 months or unstable angina (angina symptoms at rest) or clinically significant cardiac arrhythmias QTc interval (using Fridericia correction calculation) > 480 msec

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Cohort 1<br>Escalating doses of CTX-8371 | Drug: CTX-8371<br>* Intravenous (IV) infusion (0.1-10.0 mg/kg) every two weeks.<br>|
| Experimental: Dose Expansion Cohort 2<br>Dose of CTX-8371 depending on Cohort 1 data | Drug: CTX-8371<br>* Intravenous (IV) infusion (0.1-10.0 mg/kg) every two weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort 1: Evaluate the safety and tolerability of escalating doses of CTX-8371 | Number of participants with dose limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), and/or changes in clinical laboratory abnormalities | From first dose of CTX-8371 (Cycle 1 Day 1, Cycle = 2 weeks) until 30 days after the last dose of CTX-8371, average of 6 months | 
| Cohort 1: Determine the dose(s) of CTX-8371 to be further examined in Phase 2 studies |  | From first dose of CTX-8371 (Cycle 1 Day 1, Cycle = 2 weeks ) until 30 days after the last dose of CTX-8371 (average of 6 months ) | 
| Cohort 2: Evaluate the safety and tolerability of CTX-8371 at dose(s) selected from Cohort 1 | Incidence of treatment-emergent adverse events (TEAEs) | From first dose of CTX-8371 (Cycle 1 Day 1, Cycle = 2 weeks) until 30 days after the last dose of CTX-8371 (up to 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) (Percentage of Participants With Objective Response) as per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 or Lugano (2014) |  | Baseline until confirmed disease progression (CR or PR) (up to 2 years) | 
| Duration of Response (DOR) as per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 or Lugano (2014) |  | From the date of first confirmed CR or PR until the first date of recurrent or progressive disease (up to 2 years | 
| Progression-Free Survival (PFS) as per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 or Lugano (2014) |  | From first dose of CTX-8371(Cycle 1 Day 1,Cycle = 2 weeks ) until disease progression or death, whichever occur first (up to 2 years) | 
| Overall Survival (OS) of CTX-8371 |  | From first dose of CTX-8371 (Cycle 1 Day 1,Cycle = 2 weeks) until death (up to 2 years) | 
| Maximum serum concentration (Cmax) of CTX-8371 |  | From first dose of CTX-8371 (Cycle 1 Day 1,Cycle = 2 weeks) until treatment discontinuation | 
| Time of maximum observed serum concentration (Tmax) of CTX-8371 |  | From first dose of CTX-8371 (Cycle 1 Day 1, Cycle = 2 weeks) until treatment discontinuation | 
| Trough serum concentration (Ctrough) of CTX-8371 |  | From first dose of CTX-8371 (Cycle 1 Day 1, Cycle = 2 weeks) until treatment discontinuation | 
| Area under the serum concentrations of CTX-8371 versus time curve (AUC) for CTX-8371 |  | From first dose of CTX-8371 (Cycle 1 Day 1,Cycle = 2 weeks) until treatment discontinuation | 
| Clearance (CL) of serum concentrations of CTX-8371 |  | From first dose of CTX-8371 (Cycle 1 Day 1, Cycle = 2 weeks) until treatment discontinuation | 
| Volume of distribution (Vd) of serum concentrations of CTX-8371 |  | From first dose of CTX-8371 (Cycle 1 Day 1, Cycle = 2 weeks) until treatment discontinuation | 
| Half-life (t1/2) of serum concentrations of CTX-8371 |  | From first dose of CTX-8371 (Cycle 1 Day 1, Cycle = 2 weeks) until treatment discontinuation | 
| Dose Response for CTX-8371 |  | From first dose of CTX-8371 (Cycle 1 Day 1, Cycle = 2 weeks) until treatment discontinuation | 
| Assess the immunogenicity of CTX-8371 | Screen for the presence and development of antibodies against CTX-8371 | From first dose of CTX-8371 (Cycle 1 Day 1, Cycle = 2 weeks) until end of treatment visit |