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
Summary
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
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 as monotherapy or in combination with paclitaxel at the dose(s) selected in Phase 1a in 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, MSS CRC, mixed solid tumor cohort indications consisting of patients with MPM, TNBC, locally advanced or metastatic urothelial cancer, cervical cancer, and DLBCL including patients with DLBCL-RT. In Arm 1 (NX-1607 monotherapy), more than 1 dose level of NX-1607 may be tested in individual indications, each of which will constitute a separate cohort in Phase 1b.
Arms & interventions
- DrugNX-1607
Oral NX-1607
- DrugPaclitaxel
Paclitaxel IV
Outcome measures
Primary
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
Time frame: 16 months
Incidence of immune-related AEs (irAEs), all deaths, and dose-limiting toxicities (DLTs)
Phase 1a
Time frame: Up to 2 Years
Objective Response Rate (ORR) per disease-specific response criteria as assessed by the Investigator
Phase 1b
Time frame: Up to 3 Years
Secondary
PK parameters of NX-1607: area under the curve (AUC)
Time frame: Up to 3 Years
PK parameters of NX-1607: apparent clearance (CL/F)
Time frame: Up to 3 Years
PK parameters of NX-1607: maximum plasma concentration (Cmax)
Time frame: Up to 3 Years
PK parameters of NX-1607: volume of distribution
Time frame: Up to 3 Years
PK parameters of NX-1607: half-life and time to maximum plasma concentration
Time frame: Up to 3 Years
PK parameters of NX-1607: accumulation ratio (Racc)
Time frame: Up to 3 Years
PD Biomarkers: Changes from baseline in inflammatory cytokine expression in the circulating immune cells
Time frame: Up to 3 Years
Objective response rate (ORR) per disease-specific response criteria as assessed by the Investigator
Time frame: Up to 3 Years
Duration of response (DOR) as assessed by the Investigator
Time frame: Up to 3 Years
Disease control rate (DCR) as assessed by the Investigator
Time frame: Up to 3 Years
Progression-free survival (PFS) as assessed by the Investigator
Time frame: Up to 3 Years
Overall survival (OS) as assessed by the Investigator
Time frame: 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
Time frame: Up to 3 Years
Time to disease progression assessed by the Investigator (according to relevant disease histology)
Time frame: Up to 3 Years
Incidence of IrAEs and all deaths
Time frame: Up to 3 Years
Time from start of treatment to disease progression based on PCWG3 criteria
Time frame: Up to 3 Years
PD Biomarkers: Changes from baseline in tumor tissue biopsies of immune cell infiltration or other histological features
Time frame: Up to 3 Years
Eligibility criteria
Study locations (10)
City of Hope
Duarte, California, 91010
University of Southern California
Los Angeles, California, 90007
University of California, San Francisco
San Francisco, California, 94158
University of Colorado School of Medicine
Aurora, Colorado, 80045
University of Chicago
Chicago, Illinois, 60637
University of North Carolina
Chapel Hill, North Carolina, 27599
University of Oklahoma
Oklahoma City, Oklahoma, 73104
MD Anderson Cancer Center
Houston, Texas, 77030
University of Virginia
Charlottesville, Virginia, 22908
Fred Hutchinson Cancer Center
Seattle, Washington, 98109
References
- Wolf D, Baier G. IFNgamma Helps CBLB-Deficient CD8+ T Cells to Put Up Resistance to Tregs. Cancer Immunol Res. 2022 Apr 1;10(4):370. doi: 10.1158/2326-6066.CIR-22-0080.(PubMed)