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A Study of NX-1607 in Adults With Advanced Malignancies

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ClinicalTrials.gov Identifier: NCT05107674
Recruitment Status : Recruiting
First Posted : November 4, 2021
Last Update Posted : December 13, 2021
Sponsor:
Information provided by (Responsible Party):
Nurix Therapeutics, Inc.

Brief 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.

Condition or disease Intervention/treatment Phase
Ovarian Cancer, Epithelial Gastric Cancer GastroEsophageal Junction (GEJ) Cancer Head and Neck Squamous Cell Carcinoma Metastatic 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 Colorectal Cancer Metastatic CLL Transformation Richter Syndrome Drug: NX-1607 Phase 1

Detailed Description:

Phase 1a is a dose escalation to 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 include platinum resistant epithelial ovarian cancer (EOC), gastric/gastroesophageal junction (GEJ) cancer, squamous cell carcinoma of the head and neck (HNSCC), metastatic 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).

Phase 1b will investigate the efficacy of NX-1607 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
  • 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
  • Diffuse large cell B-cell lymphoma with Richter transformation (DLBCL-RT)

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 336 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : September 29, 2021
Estimated Primary Completion Date : August 31, 2024
Estimated Study Completion Date : February 28, 2025


Arm Intervention/treatment
Experimental: Phase 1a Dose Escalation
Multiple dose levels of NX-1607 to be evaluated; determination of MTD/Phase 1b recommended dose
Drug: NX-1607
Oral NX-1607, once daily
Other Name: Cbl-b Inhibitor

Experimental: Phase 1b Dose Expansion in platinum-resistant EOC
Patients with platinum-resistant EOC, including primary peritoneal and fallopian tube carcinoma
Drug: NX-1607
Oral NX-1607, once daily
Other Name: Cbl-b Inhibitor

Experimental: Phase 1b Dose Expansion in advanced gastric/GEJ cancer
Patients with recurrent, locally advanced, or metastatic gastric or GEJ adenocarcinoma
Drug: NX-1607
Oral NX-1607, once daily
Other Name: Cbl-b Inhibitor

Experimental: Phase 1b Dose Expansion in HNSCC
Patients with recurrent, locally advanced, or metastatic HNSCC
Drug: NX-1607
Oral NX-1607, once daily
Other Name: Cbl-b Inhibitor

Experimental: Phase 1b Dose Expansion in unresectable or metastatic melanoma
Patients with Stage IVa, IVb, or IVc Melanoma
Drug: NX-1607
Oral NX-1607, once daily
Other Name: Cbl-b Inhibitor

Experimental: Phase 1b Dose Expansion in advanced NSCLC
Patients with Stage IV adenocarcinoma NSCLC
Drug: NX-1607
Oral NX-1607, once daily
Other Name: Cbl-b Inhibitor

Experimental: Phase 1b Dose Expansion in mCRPC
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 progression
Drug: NX-1607
Oral NX-1607, once daily
Other Name: Cbl-b Inhibitor

Experimental: Phase 1b Dose Expansion in mixed solid tumor cohort
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
Oral NX-1607, once daily
Other Name: Cbl-b Inhibitor

Experimental: Phase 1b Dose Expansion in DLBCL-RT
Patients with DLBCL-RT previously treated with at least 1 line of standard, systemic chemotherapy, are not candidates for standard treatment options, or will otherwise be prevented from receiving any standard treatment options
Drug: NX-1607
Oral NX-1607, once daily
Other Name: Cbl-b Inhibitor




Primary Outcome Measures :
  1. 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 [ Time Frame: 16 months ]
    Phase 1a

  2. Incidence of immune-related AEs (irAEs), all deaths, and dose-limiting toxicities (DLTs) [ Time Frame: Up to 2 Years ]
    Phase 1a

  3. Objective Response Rate (ORR) per disease-specific response criteria as assessed by the Investigator [ Time Frame: Up to 3 Years ]
    Phase 1b


Secondary Outcome Measures :
  1. PK parameters of NX-1607: area under the curve (AUC) [ Time Frame: Up to 3 Years ]
    Phase 1a/1b - Sampling following the first dose, pre and post-dose at selected cycles, and at the end of treatment

  2. PK parameters of NX-1607: apparent clearance (CL/F) [ Time Frame: Up to 3 Years ]
    Phase 1a/1b - Sampling following the first dose, pre and post-dose at selected cycles, and at the end of treatment

  3. PK parameters of NX-1607: maximum plasma concentration (Cmax) [ Time Frame: Up to 3 Years ]
    Phase 1a/1b - Sampling following the first dose, pre and post-dose at selected cycles, and at the end of treatment

  4. PK parameters of NX-1607: volume of distribution [ Time Frame: Up to 3 Years ]
    Phase 1a/1b - Sampling following the first dose, pre and post-dose at selected cycles, and at the end of treatment

  5. PK parameters of NX-1607: half-life and time to maximum plasma concentration [ Time Frame: Up to 3 Years ]
    Phase 1a/1b - Sampling following the first dose, pre and post-dose at selected cycles, and at the end of treatment

  6. PK parameters of NX-1607: accumulation ratio (Racc) [ Time Frame: Up to 3 Years ]
    Phase 1a/1b - Sampling following the first dose, pre and post-dose at selected cycles, and at the end of treatment

  7. PD Biomarkers: Changes from baseline in inflammatory cytokine expression in the circulating immune cells [ Time Frame: Up to 3 Years ]
    Phase 1a/1b - Sampling following the first dose, pre and post-dose at selected cycles, and at the end of treatment

  8. Objective response rate (ORR) per disease-specific response criteria as assessed by the Investigator [ Time Frame: Up to 3 Years ]
    Phase 1a

  9. Duration of response (DOR) as assessed by the Investigator [ Time Frame: Up to 3 Years ]
    Phase 1a/1b

  10. Disease control rate (DCR) as assessed by the Investigator [ Time Frame: Up to 3 Years ]
    Phase 1a/1b

  11. Progression-free survival (PFS) as assessed by the Investigator [ Time Frame: Up to 3 Years ]
    Phase 1a/1b

  12. Overall survival (OS) as assessed by the Investigator [ Time Frame: Up to 3 Years ]
    Phase 1a/1b

  13. 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 ]
    Phase 1b

  14. Time to disease progression assessed by the Investigator (according to relevant disease histology) [ Time Frame: Up to 3 Years ]
    Phase 1b

  15. Incidence of IrAEs and all deaths [ Time Frame: Up to 3 Years ]
    Phase 1b

  16. Time from start of treatment to disease progression based on PCWG3 criteria [ Time Frame: Up to 3 Years ]
    Phase 1b (mCRPC cohort only)

  17. PD Biomarkers: Changes from baseline in inflammatory cytokine levels in the tumor micro-environment [ Time Frame: Up to 3 Years ]
    Phase 1b



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 nitroureas, 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-RT (Phase 1b only).
  • Accessible tumor or lymph node (e.g., DLBCL-RT) for biopsy (Phase 1b only).

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.
    • History of known or suspected seizure disorder.
  • 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 or social situation that would limit compliance with study requirements.
  • Prior treatment with a CPI (anti-PD-1, PD-L1, CTLA-4, etc.) within 3 weeks prior to the first dose of study drug.
  • History of chimeric antigen receptor T-cell (CAR-T) therapy within 100 days prior to the first dose of study drug. Must have evidence of B-cell recovery if prior CAR-T therapy.
  • 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.
  • 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 study drug.
  • Known allergies, hypersensitivity, or intolerance to components of study drug.
  • Pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of study drug.
  • Patient is a man who plans to father a child while enrolled in this study or within 3 months after the last dose of study drug.
  • Patient has had major surgery (e.g., requiring general anesthesia) within 4 weeks before the planned first dose of study drug, 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 study drug. 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 study drug.
  • 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 liver disease from any cause, 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), or other immunosuppressive drugs within 30 days, prior to the first dose of study drug.
  • 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 investigational product (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 study drug.
  • Any of the following within 6 months prior to the first dose of study drug:

    • 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
  • Use, within 14 days prior to the first dose of study drug, or the need for concomitant treatment with, a potent or moderate inhibitor or inducer of CYP3A4 or sensitive P glycoprotein substrate.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05107674


Contacts
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Contact: Nurix Therapeutics Patient Outreach 4152307815 ext 7815 nx1607101@nurix.com

Locations
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United Kingdom
Royal Marsden Hospital NHS Foundation Trust Recruiting
Sutton, Surrey, United Kingdom, SM2 5PT
Sarah Cannon Research Institute Recruiting
London, United Kingdom, W1G 6AD
Sponsors and Collaborators
Nurix Therapeutics, Inc.
Investigators
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Study Director: Robert J Brown Nurix Therapeutics, Inc.
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Responsible Party: Nurix Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT05107674    
Other Study ID Numbers: NX-1607-101
First Posted: November 4, 2021    Key Record Dates
Last Update Posted: December 13, 2021
Last Verified: December 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Nurix Therapeutics, Inc.:
Ubiquitin Ligase Inhibitor
Advanced Malignancies
T-cell Activation
Additional relevant MeSH terms:
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Carcinoma
Neoplasms
Triple Negative Breast Neoplasms
Mesothelioma
Mesothelioma, Malignant
Squamous Cell Carcinoma of Head and Neck
Carcinoma, Ovarian Epithelial
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Urogenital Neoplasms
Neoplasms by Site
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Squamous Cell
Ovarian Neoplasms
Endocrine Gland Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Neoplasms, Female
Endocrine System Diseases
Gonadal Disorders
Breast Neoplasms
Breast Diseases
Skin Diseases
Adenoma
Neoplasms, Mesothelial
Pleural Neoplasms