NX-1607 for Advanced Cancer

Recruiting at19 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Nurix Therapeutics, Inc.

Must not be taking: CYP3A4 inducers, inhibitors, Biotin

Disqualifiers: Untreated brain metastases, Uncontrolled illness, Active infection, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing NX-1607, a new experimental drug, in adults with advanced cancers that don't respond to standard treatments. The goal is to see if NX-1607 can safely stop or reduce cancer growth, either by itself or with another drug called paclitaxel. Paclitaxel is a widely used anti-cancer drug for treating various types of solid malignant tumors including breast, ovarian, and lung cancers.

Will I have to stop taking my current medications?

The trial requires a minimum of 3 weeks or 5 half-lives since the last dose of systemic cancer therapy, and certain medications like strong or moderate CYP3A4 inducers or inhibitors must be stopped 14 or 7 days prior, respectively. You may need to stop some medications, but the protocol does not specify all medications that must be stopped.

What evidence supports the effectiveness of the drug NX-1607 for treating advanced cancer?

The research on Cbl-b inhibitors, like those in NX-1607, suggests they may help treat cancer by blocking certain proteins that allow cancer cells to survive. Although not directly about NX-1607, studies on similar compounds show potential in making cancer cells more sensitive to treatment. ^{1 2 3 4 5}

What makes the drug NX-1607 unique for treating advanced cancer?

NX-1607 is unique because it targets a specific protein involved in cancer cell growth, potentially offering a new approach compared to traditional treatments. This drug may work differently by focusing on a novel mechanism of action, which could provide benefits for patients with advanced cancer. ^{6 7 8 9 10}

Research Team

Linda Neuman, MD

Principal Investigator

Nurix Therapeutics, Inc.

Eligibility Criteria

Adults with certain advanced cancers (like ovarian, stomach, lung, prostate cancer and more) who have tried standard treatments without success or can't receive them. They must be over 18, not pregnant or breastfeeding, willing to use contraception and follow study rules. People with active brain metastases, recent major surgery or immunotherapy side effects are excluded.

Inclusion Criteria

My cancer has spread or can't be removed and I've tried, can't have, or can't get standard treatments.

It's been enough time since my last cancer treatment.

I can have a biopsy on my tumor or lymph node (if I have DLBCL).

Exclusion Criteria

Known allergies, hypersensitivity, or intolerance to components of NX-1607

I haven't had a live vaccine in the last 28 days or a COVID-19 vaccine in the last 14 days.

I cannot take pills by mouth or have serious digestive system issues.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1a Dose Escalation

Evaluation of safety and tolerability of NX-1607 in adult patients with advanced solid tumors, including monotherapy and combination with Paclitaxel

16 months

Phase 1b Dose Expansion

Investigation of the efficacy of NX-1607 as monotherapy or in combination with Paclitaxel in select advanced malignancies

Up to 3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• NX-1607 (Other)

Trial Overview The trial is testing NX-1607 alone or with Paclitaxel in patients with various advanced malignancies. It's a first-in-human study assessing safety and how well the drug works against cancer.

Participant Groups

Group I: Phase 1b Dose Expansion of NX-1607 in combination with Paclitaxel Experimental Treatment 2 Interventions

Indications may include but are not limited to, platinum resistant EOC, gastric/GEJ cancer, HSNCC, NSCLC, TNBC, and locally advanced or metastatic urothelial cancer and cervical cancer

Group II: Phase 1b Dose Expansion in recurrent melanoma Experimental Treatment 1 Intervention

Patients with recurrent and either metastatic or unresectable Melanoma

Group III: Phase 1b Dose Expansion in platinum-resistant EOC Experimental Treatment 1 Intervention

Patients with platinum-resistant EOC, including primary peritoneal and fallopian tube carcinoma

Group IV: Phase 1b Dose Expansion in mixed solid tumor cohort Experimental Treatment 1 Intervention

Cohort of mixed solid tumor indications consisting of patients with MPM, TNBC, locally advanced or metastatic urothelial cancer, cervical cancer, or DLBCL/DLBCL-RT

Group V: Phase 1b Dose Expansion in mCRPC Experimental Treatment 1 Intervention

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

Group VI: Phase 1b Dose Expansion in advanced gastric/GEJ cancer Experimental Treatment 1 Intervention

Patients with recurrent, locally advanced, or metastatic gastric or GEJ adenocarcinoma

Group VII: Phase 1b Dose Expansion in advanced NSCLC Experimental Treatment 1 Intervention

Patients with Stage IV NSCLC

Group VIII: Phase 1b Dose Expansion in MSS CRC Experimental Treatment 1 Intervention

Patients with histologically confirmed MSS CRC, known KRAS WT, and must have been previously treated with \> = 2 lines of systemic therapy including a fluoropyrimidine, irinotecan, and/or oxaliplatin (and EGFR inhibitor if known Ras wild type)

Group IX: Phase 1b Dose Expansion in HNSCC Experimental Treatment 1 Intervention

Patients with recurrent, locally advanced, or metastatic HNSCC

Group X: Phase 1a Food Effect Experimental Treatment 1 Intervention

Impact of food on NX-1607 bioavailability and tolerability to be evaluated

Group XI: Phase 1a Dose Escalation of NX-1607 in combination with Paclitaxel Experimental Treatment 2 Interventions

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.

Group XII: Phase 1a Dose Escalation of NX-1607 (monotherapy) Experimental Treatment 1 Intervention

Multiple dose levels and dosing regimen of NX-1607 to be evaluated; determination of MTD/Phase 1b recommended dose.

Who Is Running the Clinical Trial?

Nurix Therapeutics, Inc.

Lead Sponsor

Trials

7

Recruited

1,100+

Findings from Research

The study introduces new lactam compounds that act as inhibitors of Cbl-b, a protein that can regulate immune responses, potentially enhancing the body's ability to fight cancer.

These novel compounds may offer a new therapeutic approach for cancer treatment, although further details on their efficacy and safety in clinical settings are not provided in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Lactams as Cbl-b Inhibitors for Treating Cancer. Sabnis, RW.[2023]

In small cell lung cancer cell lines, higher levels of Noxa and Bcl-2 were linked to increased sensitivity to the BH3 mimetic drug ABT-737, while Mcl-1 levels remained constant across different sensitivities.

Noxa expression was found to be a key factor in determining sensitivity to ABT-737, as its enforced expression enhanced drug sensitivity, and it may play a direct role in promoting apoptosis induced by ABT-737, despite not consistently regulating Mcl-1 levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737. Hauck, P., Chao, BH., Litz, J., et al.[2020]

ABT-737, a drug targeting the anti-apoptotic protein Bcl-x(L), was ineffective alone in promoting cell death in ovarian cancer cell lines, but became effective when combined with Mcl-1 inhibitors, highlighting the importance of targeting multiple anti-apoptotic pathways.

Platinum compounds can enhance the effectiveness of ABT-737 by reducing Mcl-1 levels and increasing pro-apoptotic proteins like Noxa, leading to significant cell death in chemoresistant ovarian cancer cells, suggesting a promising combination therapy for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Platinum compounds sensitize ovarian carcinoma cells to ABT-737 by modulation of the Mcl-1/Noxa axis. Simonin, K., N'Diaye, M., Lheureux, S., et al.[2016]

In a phase I trial involving 29 patients with relapsed or refractory chronic lymphocytic leukemia (CLL), the novel drug navitoclax significantly reduced lymphocytosis by over 50% in 19 out of 21 patients, demonstrating its potential efficacy in targeting BCL2 overexpression.

Navitoclax was well-tolerated at a dose of 250 mg/day, with 35% of patients achieving a partial response and a median progression-free survival of 25 months, indicating its promise as a therapeutic option for CLL, especially in patients with challenging disease characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. Roberts, AW., Seymour, JF., Brown, JR., et al.[2022]

ABT-199, a Bcl-2-selective drug, was found to be highly effective against primary mantle cell lymphoma (MCL) samples, with a low lethal dose (LD50 < 10 nM), while only a few MCL cell lines showed sensitivity (LD50 < 200 nM).

Resistance to ABT-199 in MCL cells can be influenced by their microenvironment, but this resistance is lost when cells detach from protective fibroblasts, suggesting that combining ABT-199 with BTK inhibitors could enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma. Chiron, D., Dousset, C., Brosseau, C., et al.[2021]

The conjugate chA7Fab-NCS, formed by binding the anticancer agent neocarzinostatin to a chimeric antibody fragment, was found to be 2.3 times more effective than free neocarzinostatin in inhibiting the growth of human pancreatic carcinoma cells that express the A7 antibody target.

ChA7Fab-NCS demonstrated similar antitumor activity to free neocarzinostatin in pancreatic carcinoma cells that do not express the A7 target, suggesting its potential as an effective immunotargeted chemotherapy option for treating pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor effect of neocarzinostatin conjugated to human/mouse chimeric Fab fragments of the monoclonal antibody A7 on human pancreatic carcinoma. Otsuji, E., Yamaguchi, T., Yata, Y., et al.[2019]

AB680 is a potent human CD73 inhibitor currently undergoing a Phase I clinical trial for solid tumors, demonstrating a promising approach in cancer treatment.

The drug acts as a reversible, slow-onset competitive inhibitor of CD73, with a very low inhibition constant (Ki) of 5 pM, indicating its strong binding affinity and potential effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Exceptionally Potent Inhibitor of Human CD73. Bowman, CE., da Silva, RG., Pham, A., et al.[2020]

B7-H3 is identified as a promising target for monoclonal antibody-based immunotherapy in cancer due to its limited expression in normal tissues and association with poor prognosis in tumors, making it a potential marker for targeted treatment.

Targeting B7-H3 is expected to be both effective and safe, but further research is needed to explore its expression in various cancer-related contexts, including pre-malignant lesions and cancer initiating cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B7-H3 targeted antibody-based immunotherapy of malignant diseases. Michelakos, T., Kontos, F., Barakat, O., et al.[2023]

The high-affinity monoclonal antibody m-323/A3 demonstrated significantly better tumor targeting and delivered a higher cumulative radiation dose (2.5- to 4.7-fold more) to human ovarian cancer xenografts compared to the low-affinity antibody c-17-1A, indicating its potential for more effective radioimmunotherapy.

However, when radiation doses were adjusted to deliver similar amounts to the tumors, c-17-1A showed superior effectiveness in inhibiting tumor growth across all tested xenografts, suggesting that factors beyond just antibody affinity may influence therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of monoclonal antibodies 17-1A and 323/A3: the influence of the affinity on tumour uptake and efficacy of radioimmunotherapy in human ovarian cancer xenografts. Kievit, E., Pinedo, HM., Schlüper, HM., et al.[2022]

The 111In-labeled antibody 067-213 effectively binds to cancer cells with high CD73 expression, allowing for noninvasive imaging of CD73 levels, which is crucial for selecting patients for CD73-targeted therapies.

In studies with tumor-bearing mice, the probe showed high uptake in tumors with high CD73 expression and low uptake in normal organs, suggesting it is safe and effective for monitoring CD73 in cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiolabeled Human Monoclonal Antibody 067-213 has the Potential for Noninvasive Quantification of CD73 Expression. Sudo, H., Tsuji, AB., Sugyo, A., et al.[2020]

References

1. United States pubmed.ncbi.nlm.nih.gov

Novel Lactams as Cbl-b Inhibitors for Treating Cancer. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737. [2020]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Platinum compounds sensitize ovarian carcinoma cells to ABT-737 by modulation of the Mcl-1/Noxa axis. [2016]

4. United States pubmed.ncbi.nlm.nih.gov

Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Antitumor effect of neocarzinostatin conjugated to human/mouse chimeric Fab fragments of the monoclonal antibody A7 on human pancreatic carcinoma. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

An Exceptionally Potent Inhibitor of Human CD73. [2020]

8. England pubmed.ncbi.nlm.nih.gov

B7-H3 targeted antibody-based immunotherapy of malignant diseases. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Comparison of monoclonal antibodies 17-1A and 323/A3: the influence of the affinity on tumour uptake and efficacy of radioimmunotherapy in human ovarian cancer xenografts. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Radiolabeled Human Monoclonal Antibody 067-213 has the Potential for Noninvasive Quantification of CD73 Expression. [2020]