A Study of NX-1607 in Adults With Advanced Malignancies

Study Overview
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Brief Summary
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This is a first-in-human Phase 1a/1b multicenter, open-label oncology study designed to evaluate the safety and anti-cancer activity of NX-1607 in patients with advanced malignancies.

Detailed Description
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Phase 1a will consist of 2 study arms: Monotherapy and Paclitaxel combo. Phase 1a dose escalation will evaluate the safety and tolerability of NX-1607 in adult patients with advanced solid tumors for which standard therapy with proven clinical benefit does not exist, is no longer effective, or is not appropriate. Indications for monotherapy include platinum resistant epithelial ovarian cancer (EOC), gastric/gastroesophageal junction (GEJ) cancer, squamous cell carcinoma of the head and neck (HNSCC), recurrent and either metastatic or unresectable melanoma, non-small cell lung cancer (NSCLC), metastatic castration-resistant prostate cancer (mCRPC), malignant pleural mesothelioma (MPM), triple-negative breast cancer (TNBC), locally advanced or metastatic urothelial cancer, cervical cancer, and microsatellite stable colorectal cancer (MSS CRC), and diffuse large cell B-cell lymphoma (DLBCL) including patients with Richter transformation (DLBCL-RT). Indications for paclitaxel combo may include, but are not limited to, platinum-resistant EOC, gastric/GEJ cancer, HNSCC, NSCLC, TNBC, locally advanced or metastatic urothelial cancer, and cervical cancer at the Sponsor's discretion. Phase 1b will investigate the efficacy of NX-1607 monotherapy at the dose selected in Phase 1a in up to 8 cohorts of patients with select advanced malignancies for which standard therapy, including immunotherapy, with proven clinical benefit does not exist, is no longer effective, or is not appropriate. Indications include platinum-resistant EOC, including primary peritoneal and fallopian tube carcinoma, advanced gastric/GEJ cancer, HNSCC, recurrent and either metastatic or unresectable melanoma, advanced NSCLC, mCRPC, mixed solid tumor cohort indications consisting of patients with MPM, TNBC, locally advanced or metastatic urothelial cancer, cervical cancer, or MSS CRC, and DLBCL including patients with DLBCL-RT.

Official Title
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A Phase 1a, Dose Escalation, Safety and Tolerability Study of NX-1607, a Casitas B-lineage Lymphoma Proto-oncogene (CBL-B) Inhibitor, in Adults With Advanced Malignancies, With Phase 1b Expansion in Select Tumor Types

Conditions
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Ovarian Cancer, Epithelial, Gastric Cancer, GastroEsophageal Junction (GEJ) Cancer, Head and Neck Squamous Cell Carcinoma, Metastatic or Unresectable Melanoma, Non-small Cell Lung Cancer (NSCLC), Metastatic Castration-resistant Prostate Cancer (mCRPC), Malignant Pleural Mesothelioma (MPM), Triple Negative Breast Cancer (TNBC), Metastatic Urothelial Carcinoma, Cervical Cancer, Diffuse Large B Cell Lymphoma (DLBCL), Richter Transformation, Microsatellite Stable Colorectal Carcinoma

Intervention / Treatment
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* Drug: NX-1607
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Age ≥ 18 years. Measurable disease per disease-specific response criteria. Patients must have disease that is metastatic or unresectable and have received standard treatment options, are not candidates for standard treatment options, or will otherwise be prevented from receiving any standard treatment options. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Minimum of 3 weeks or 5 half-lives (whichever is shorter) since last dose of systemic cancer therapy (unless otherwise specified) or minimum of 2 weeks since last radiotherapy, or minimum of 6 weeks since last systemic therapy with nitrosoureas, antibody-drug conjugate, or radio immuno-conjugate therapy. Adequate organ and bone marrow function, in the absence of growth factors, as defined by laboratory parameters. Patients of child-bearing potential must use adequate contraceptive measures to avoid pregnancy for the duration of the study as defined in the protocol. Patient must be willing and able to adhere to the prohibitions and restrictions specified in the protocol. Each patient must sign an informed consent form (ICF). Histological or cytological diagnosis of platinum-resistant EOC, including primary peritoneal and fallopian tube carcinoma; gastric/GEJ cancer; HNSCC; metastatic or unresectable melanoma; NSCLC; mCRPC; MPM; TNBC; locally advanced or metastatic urothelial cancer; cervical cancer; MSS CRC; or DLBCL (including DLBCL-RT) Accessible tumor (for all cohorts) or lymph node (DLBCL only) for biopsy (Phase 1b only). Key Exclusion Criteria: Active untreated brain metastases. Patient has any of the following: Uncontrolled intercurrent illness including, but not limited to, poorly controlled hypertension or diabetes, or ongoing active infection requiring systemic therapy. Patients with primary refractory EOC defined as patients who do not respond to their first platinum-containing regimen or who relapse less than 6 months after completion of that first platinum-containing regimen Psychiatric illness that would limit compliance with study requirements. Prior treatment with a CPI (anti-PD-1, PD-L1, cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], etc.) within 3 weeks prior to the first dose of NX-1607. History of CAR-T therapy within 30 days prior to the first dose of NX-1607. Toxicities from previous anti-cancer therapies that have not resolved to baseline levels or to Grade 1 or less except for Grade 2 alopecia and Grade 2 peripheral neuropathy or patients receiving endocrine replacement therapy Patients who experienced Grade 3 or higher irAEs with prior immunotherapy. History of uveitis, or an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. Unable to swallow capsules or has malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction likely to interfere with the delivery, absorption, or metabolism of NX-1607. Known allergies, hypersensitivity, or intolerance to components of NX-1607. Pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of NX-1607. Patient is a man who plans to father a child while enrolled in this study or within 3 months after the last dose of NX-1607 and, as applicable, within 6 months after the last dose of paclitaxel. Patient has had major surgery (e.g., requiring general anesthesia) within 4 weeks before the planned first dose of NX-1607, or will not have fully recovered from surgery, or has surgery planned during the time the patient is expected to participate in the study or within 4 weeks after the last dose of NX-1607. Note: Patients with minor planned surgical procedures to be conducted under local anesthesia may participate. Vaccinated with a live vaccine within 28 days (with the exception of the annual inactivated influenza vaccine) prior to the first dose of NX-1607. Active known second malignancy with the exception of any of the following: Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer. Adequately treated Stage I cancer from which the patient is currently in remission and has been in remission for ≥ 2 years. Low-risk prostate cancer with Gleason score < 7 and PSA < 10 ng/mL. Any other cancer from which the patient has been disease-free for ≥ 2 years. Infection with human immunodeficiency virus (HIV)-1 or HIV-2. Exception: Patients with well controlled HIV (e.g., CD4 > 350/mm3 and undetectable viral load) are eligible. Current active hepatitis, including hepatitis A (hepatitis A virus immunoglobulin M [IgM] positive), hepatitis B (hepatitis B virus [HBV] surface antigen positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV RNA). Patients with HCV with undetectable virus after treatment are eligible. Patients with prior exposure to HBV may be entered if quantitative PCR is negative. Use of systemic corticosteroids (> 20 mg prednisone or equivalent) within 15 days (except for prophylaxis for radio diagnostic contrast reactions and/or prophylaxis for patients receiving paclitaxel), or other immunosuppressive drugs within 30 days, prior to the first dose of NX-1607. Use of biotin (i.e., Vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 µg [NIH 2020] (Note: Patients who switch from a high dose to a dose of 30 µg/day or less at least 1 day prior to Screening assessments are eligible for study entry). Receipt of an IP or has been treated with an investigational device within 3 weeks or 5 half-lives (whichever is shorter) prior to the first dose of NX-1607. Any of the following within 6 months prior to the first dose of NX-1607: Myocardial infarction Unstable angina Unstable symptomatic ischemic heart disease New York Heart Association Class III or IV heart failure Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events) Any other significant cardiac condition (e.g., pericardial effusion, restrictive cardiomyopathy, severe untreated valvular stenosis, or severe congenital heart disease) Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating Investigator in consultation with the Medical Monitor. Use, within 14 days prior to the first dose of NX-1607, or the need for concomitant treatment with, a potent or moderate inhibitor or inducer of CYP3A4 (and CYP2C8 for Paclitaxel combination only), or a sensitive substrate of CYP3A4 The need for concomitant treatment with a sensitive substrate of P-gp or BCRP.

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: Phase 1a Dose Escalation of NX-1607 (monotherapy)<br>Multiple dose levels and dosing regimen of NX-1607 to be evaluated; determination of MTD/Phase 1b recommended dose. | Drug: NX-1607<br>* Oral NX-1607<br>* Other names: Cbl-b Inhibitor;|
| Experimental: Phase 1a Food Effect<br>Impact of food on NX-1607 bioavailability and tolerability to be evaluated | Drug: NX-1607<br>* Oral NX-1607<br>* Other names: Cbl-b Inhibitor;|
| Experimental: Phase 1b Dose Expansion in platinum-resistant EOC<br>Patients with platinum-resistant EOC, including primary peritoneal and fallopian tube carcinoma | Drug: NX-1607<br>* Oral NX-1607<br>* Other names: Cbl-b Inhibitor;|
| Experimental: Phase 1b Dose Expansion in advanced gastric/GEJ cancer<br>Patients with recurrent, locally advanced, or metastatic gastric or GEJ adenocarcinoma | Drug: NX-1607<br>* Oral NX-1607<br>* Other names: Cbl-b Inhibitor;|
| Experimental: Phase 1b Dose Expansion in HNSCC<br>Patients with recurrent, locally advanced, or metastatic HNSCC | Drug: NX-1607<br>* Oral NX-1607<br>* Other names: Cbl-b Inhibitor;|
| Experimental: Phase 1b Dose Expansion in recurrent melanoma<br>Patients with recurrent and either metastatic or unresectable Melanoma | Drug: NX-1607<br>* Oral NX-1607<br>* Other names: Cbl-b Inhibitor;|
| Experimental: Phase 1b Dose Expansion in advanced NSCLC<br>Patients with Stage IV adenocarcinoma NSCLC | Drug: NX-1607<br>* Oral NX-1607<br>* Other names: Cbl-b Inhibitor;|
| Experimental: Phase 1b Dose Expansion in mCRPC<br>Patients with mCRPC who received a minimum of 2 prior lines of therapy in the advanced setting including androgen receptor-directed therapy and a taxane-based chemotherapy and has PSA or radiographic progression | Drug: NX-1607<br>* Oral NX-1607<br>* Other names: Cbl-b Inhibitor;|
| Experimental: Phase 1b Dose Expansion in mixed solid tumor cohort<br>Cohort of mixed solid tumor indications consisting of patients with MPM, TNBC, locally advanced or metastatic urothelial cancer, cervical cancer, or MSS CRC | Drug: NX-1607<br>* Oral NX-1607<br>* Other names: Cbl-b Inhibitor;|
| Experimental: Phase 1b Dose Expansion in DLBCL including DLBCL-RT<br>Patients with DLBCL or DLBCL-RT, previously treated with standard, systemic chemotherapy, are not candidates for standard treatment options, or will otherwise be prevented from receiving any standard treatment options. | Drug: NX-1607<br>* Oral NX-1607<br>* Other names: Cbl-b Inhibitor;|
| Experimental: Phase 1a Dose Escalation of NX-1607 in combination with Paclitaxel<br>Indications may include but are not limited to, platinum resistant EOC, gastric/GEJ cancer. HSNCC, NSCLC, TNBC, locally advanced or metastatic urothelial cancer and cervical cancer. | Drug: NX-1607<br>* Oral NX-1607<br>* Other names: Cbl-b Inhibitor;Drug: Paclitaxel<br>* Paclitaxel IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (TEAEs), including Grade ≥ 3 TEAEs, treatment-emergent serious adverse events (SAEs), TEAEs leading to study drug discontinuation, and deaths due to TEAEs | Phase 1a | 16 months | 
| Incidence of immune-related AEs (irAEs), all deaths, and dose-limiting toxicities (DLTs) | Phase 1a | Up to 2 Years | 
| Objective Response Rate (ORR) per disease-specific response criteria as assessed by the Investigator | Phase 1b | Up to 3 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK parameters of NX-1607: area under the curve (AUC) | Phase 1a/1b - Sampling following the first dose, pre and post-dose at selected cycles, and at the end of treatment | Up to 3 Years | 
| PK parameters of NX-1607: apparent clearance (CL/F) | Phase 1a/1b - Sampling following the first dose, pre and post-dose at selected cycles, and at the end of treatment | Up to 3 Years | 
| PK parameters of NX-1607: maximum plasma concentration (Cmax) | Phase 1a/1b - Sampling following the first dose, pre and post-dose at selected cycles, and at the end of treatment | Up to 3 Years | 
| PK parameters of NX-1607: volume of distribution | Phase 1a/1b - Sampling following the first dose, pre and post-dose at selected cycles, and at the end of treatment | Up to 3 Years | 
| PK parameters of NX-1607: half-life and time to maximum plasma concentration | Phase 1a/1b - Sampling following the first dose, pre and post-dose at selected cycles, and at the end of treatment | Up to 3 Years | 
| PK parameters of NX-1607: accumulation ratio (Racc) | Phase 1a/1b - Sampling following the first dose, pre and post-dose at selected cycles, and at the end of treatment | Up to 3 Years | 
| PD Biomarkers: Changes from baseline in inflammatory cytokine expression in the circulating immune cells | Phase 1a/1b - Sampling following the first dose, pre and post-dose at selected cycles, and at the end of treatment | Up to 3 Years | 
| Objective response rate (ORR) per disease-specific response criteria as assessed by the Investigator | Phase 1a | Up to 3 Years | 
| Duration of response (DOR) as assessed by the Investigator | Phase 1a/1b | Up to 3 Years | 
| Disease control rate (DCR) as assessed by the Investigator | Phase 1a/1b | Up to 3 Years | 
| Progression-free survival (PFS) as assessed by the Investigator | Phase 1a/1b | Up to 3 Years | 
| Overall survival (OS) as assessed by the Investigator | Phase 1a/1b | Up to 3 Years | 
| Incidence of TEAEs, including Grade ≥ 3 TEAEs, treatment emergent SAEs, TEAEs leading to study drug discontinuation, and deaths due to TEAEs | Phase 1b | Up to 3 Years | 
| Time to disease progression assessed by the Investigator (according to relevant disease histology) | Phase 1b | Up to 3 Years | 
| Incidence of IrAEs and all deaths | Phase 1b | Up to 3 Years | 
| Time from start of treatment to disease progression based on PCWG3 criteria | Phase 1b (mCRPC cohort only) | Up to 3 Years | 
| PD Biomarkers: Changes from baseline in tumor tissue biopsies of immune cell infiltration or other histological features | Phase 1b | Up to 3 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ubiquitin Ligase Inhibitor, Advanced Malignancies, T-cell Activation