KSQ-4279 for Advanced Cancer

Not currently recruiting at 33 trial locations

Overseen By Reference Study ID Number: WP45169 https://forpatients.roche.com/

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: KSQ Therapeutics, Inc.

Must not be taking: CYP3A4 inhibitors, inducers

Disqualifiers: Pregnancy, HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new cancer treatment called KSQ-4279, an experimental therapy for individuals with advanced solid tumors. The goal is to assess its safety and effectiveness, both alone and in combination with other drugs like Olaparib and Carboplatin. The trial also examines different administration methods, including the impact of food on the treatment. It may suit those with advanced cancer who have exhausted other treatments or lack standard options. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive it.

Will I have to stop taking my current medications?

The trial requires that you do not take strong or moderate CYP3A4 inhibitors or inducers. If you are on these medications, you must stop them for a period of 5 half-lives before starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the treatment RO7623066 is promising in terms of safety for patients with advanced cancers. Studies have found that when used alone, RO7623066 has a manageable safety profile, meaning the side effects are generally tolerable for patients. In earlier tests, patients handled the treatment without reaching a dose that was too harmful, suggesting it is relatively safe.

When combined with other drugs like carboplatin and olaparib, RO7623066 also maintains an acceptable safety profile. Patients generally handle the treatment well, without severe side effects. Notably, the combination with olaparib has effectively targeted resistant cancer cells, indicating positive clinical activity.

In summary, early research suggests that the treatment RO7623066, whether used alone or with other drugs, is well-tolerated. The side effects are considered manageable, which is encouraging for those considering participation in a clinical trial with this treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about KSQ-4279 because it offers a fresh approach to treating advanced cancer. Unlike traditional treatments, which often rely on chemotherapy or radiation, KSQ-4279 is being studied for its ability to work in combination with other drugs like olaparib and carboplatin, potentially enhancing their effectiveness. KSQ-4279 targets specific tumor mutations, which could lead to more personalized and effective cancer therapies. Additionally, the treatment's oral administration could improve patient convenience and compliance compared to intravenous options. This innovative strategy aims to not only improve outcomes but also reduce side effects by honing in on cancer's unique vulnerabilities.

What evidence suggests that this trial's treatments could be effective for advanced cancer?

Research has shown that RO7623066, one of the treatments in this trial, yields promising results in treating advanced solid tumors when used alone. In one study, 10% of patients experienced tumor shrinkage, and 42.5% maintained stable disease, meaning their cancer did not worsen. This trial also tests RO7623066 in combination with olaparib, a drug that targets certain cancers, to assess its effectiveness against tumors resistant to similar treatments. Additionally, researchers are evaluating RO7623066 with carboplatin, a common chemotherapy drug, to determine if they work better together to attack cancer cells. These early results suggest that RO7623066 could potentially treat advanced cancer. ^{1 3 6 7 8}

Who Is on the Research Team?

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Are You a Good Fit for This Trial?

Adults with advanced solid tumors that are not removable or have spread, who've tried standard treatments without success or for whom no standard treatment exists. They must be in good overall health with proper organ function and a life expectancy of at least 12 weeks. Women must use effective contraception, and men agree to barrier contraception during the study.

Inclusion Criteria

I agree to use effective birth control during and up to 3 months after the study.

My organs and bone marrow are working well.

My cancer can be measured or tracked using specific criteria.

Exclusion Criteria

Prior anticancer treatment including: Chemotherapy or small molecule-targeted therapy < 2 weeks prior to first dose of study treatment, Any antibody therapy < 5 half-lives from first dose of study treatment (or 4 weeks since last therapy, whichever is the shortest), PD-1 (anti-programmed death 1) or PD-L1 (anti-programmed death ligand 1) therapy < 4 weeks from first dose of study treatment, Invasive surgery requiring general anesthesia < 30 days from first dose of study treatment, Chemotherapy with nitrosoureas or mitomycin C, < 45 days from first dose of study treatment, Radiation therapy (including radiofrequency ablation) < 4 weeks prior to initiation of study treatment, Grade 2 or greater toxicity, except alopecia related to any prior treatment (ie, chemotherapy, targeted therapy, radiation, or surgery), Prolongation of QT/QTc interval (QTc interval > 480 msec) using the Frederica method of QTc analysis, Women who are pregnant or nursing, Seropositive for human immunodeficiency virus (HIV) 1 or 2 or acquired immunodeficiency syndrome (AIDS) or active infection with hepatitis B virus or hepatitis C virus (HCV), Other severe, acute, or chronic medical condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or that may interfere with the interpretation of the study results, and in the judgement of the Investigator, would make the patient inappropriate for the study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

RO7623066 is administered alone or in combination with other drugs to determine the maximum tolerated dose (MTD)

Variable duration until MTD is reached

Expansion

Participants receive RO7623066 at the recommended dose to further evaluate safety and clinical activity

Variable duration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 4 years 10 months

What Are the Treatments Tested in This Trial?

Interventions

• KSQ-4279

Trial Overview The trial is testing KSQ-4279 alone and combined with other therapies on patients with advanced solid tumors. It's a Phase 1 study focusing on safety and how well the drug works, starting with dose escalation to find the right amount before expanding to more patients.

How Is the Trial Designed?

Group I: RO7623066 Monotherapy (Dose Escalation) Experimental Treatment 1 Intervention

RO7623066 will be administered orally once daily (QD) continuously as monotherapy. Once the maximum tolerated dose (MTD) for RO7623066 monotherapy has been reached this concludes the Dose Escalation phase.

Group II: RO7623066 Food Effect Cohort Experimental Treatment 1 Intervention

The effect of food intake on the PK of RO7623066 will be explored at a dose close to the Maximum Tolerated Dose (MTD) and/or at Recommended Phase II Dose (RP2D) or at a relevant dose level for a minimum of 12 participants that have at least one tumor mutation of interest.

Group III: RO7623066 + Olaparib Backfill Cohort Experimental Treatment 2 Interventions

Once safety data has been obtained in the RO7623066 + Olaparib arm during the dose escalation phase, Backfill cohorts will be used to determine the Recommended Dose for Expansion of RO7623066 + Olaparib.

Group IV: RO7623066 + Olaparib (Dose Escalation and Expansion) Experimental Treatment 2 Interventions

RO7623066 will be tested in combination with olaparib. Escalating dose levels will be tested until the maximum tolerated dose (MTD), or lower, of RO7623066 is reached or MTD, or lower, of the combination is reached (whichever occurs first). Combination arms can enroll concurrently. Olaparib will be dosed per standard of care (SoC).

Group V: RO7623066 + Carboplatin (Dose Escalation and Expansion) Experimental Treatment 2 Interventions

RO7623066 will be tested in combination with carboplatin. Escalating dose levels will be tested until the maximum tolerated dose (MTD), or lower, of RO7623066 is reached or MTD, or lower, of the combination is reached (whichever occurs first). Combination arms can enroll concurrently. Carboplatin will be dosed per standard of care (SoC).

Who Is Running the Clinical Trial?

KSQ Therapeutics, Inc.

Lead Sponsor

Trials

3

Recruited

410+

Hoffmann-La Roche

Lead Sponsor

Trials

2,482

Recruited

1,107,000+

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Avastin, Herceptin, Rituxan, Accu-Chek

Dr. Levi Garraway

Hoffmann-La Roche

Chief Medical Officer since 2019

MD from the University of Basel

Dr. Thomas Schinecker

Hoffmann-La Roche

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

Published Research Related to This Trial

Targeting USP7 in advanced cancer cells, particularly those resistant to taxane treatments, effectively induces cell death and mitotic catastrophe, highlighting its potential as a therapeutic target.

Combining USP7 inhibitors with PLK1 inhibitors, like volasertib, shows strong synergistic effects in overcoming drug resistance in paclitaxel-resistant lung cancer, suggesting a promising strategy for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of Inhibitors of USP7 and PLK1 has a Strong Synergism against Paclitaxel Resistance. Shin, SB., Kim, CH., Jang, HR., et al.[2023]

USP1 is a deubiquitinating enzyme that, when overexpressed, is linked to poor prognosis in various cancers, highlighting its role in cancer progression.

Inhibiting USP1 can reduce cancer cell growth, make them more sensitive to radiation, and enhance their response to chemotherapy, suggesting it could be a promising target for combined cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of USP1 deubiquitinase in the pathogenesis and therapy of cancer. Antonenko, S., Zavelevich, M., Telegeev, G.[2023]

Hyperactivation of the deubiquitinase USP1 is linked to breast cancer metastasis, with higher levels of USP1 in primary tumors correlating with worse patient outcomes.

Inhibiting USP1 with drugs like pimozide or ML323 significantly reduces breast cancer metastasis in mouse models, highlighting the potential for USP1 inhibitors as a new treatment strategy for breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

USP1 inhibition destabilizes KPNA2 and suppresses breast cancer metastasis. Ma, A., Tang, M., Zhang, L., et al.[2022]

Ubiquitin-specific protease 2 (USP2) plays a crucial role in cancer by reversing the degradation of proteins, which affects tumor growth, migration, and resistance to treatment.

Targeting USP2 could be a promising therapeutic strategy for various cancers, including breast, liver, and prostate cancers, although more research is needed to fully understand its clinical significance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the deubiquitinase USP2 for malignant tumor therapy (Review). Zhang, S., Guo, Y., Zhang, S., et al.[2023]

Inhibition of the deubiquitinating enzyme USP1 in cancer cells, particularly those with BRCA1/2 mutations, leads to increased DNA damage and reduced DNA synthesis, highlighting its potential as a therapeutic target.

USP1 inhibition shows strong synergy with PARP inhibitors in BRCA1/2 mutant tumors, suggesting a novel treatment strategy that exploits the vulnerabilities associated with posttranslational modifications of PCNA in both BRCA1/2 mutant and certain wild-type tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ubiquitinated PCNA Drives USP1 Synthetic Lethality in Cancer. Simoneau, A., Engel, JL., Bandi, M., et al.[2023]

The study found that USP14 is overexpressed in non-small cell lung cancer (NSCLC) and other cancers, promoting tumor cell proliferation and migration, which is linked to shorter survival times.

Manipulating USP14 levels in cancer cell lines showed that reducing USP14 led to decreased cell proliferation and increased apoptosis, suggesting that targeting USP14 could be a promising strategy for cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Function of Deubiquitinating Enzyme USP14 as Oncogene in Different Types of Cancer. Zhu, Y., Zhang, C., Gu, C., et al.[2019]

USP8 levels are significantly lower in breast cancer (BC) cells compared to normal breast tissues, indicating its potential role in tumorigenesis (P < 0.0001).

Higher expression of USP8 is associated with better clinical outcomes, including improved survival rates and favorable clinical features, suggesting that USP8 may serve as a protective factor for BC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The expression of ubiquitin-specific peptidase 8 and its prognostic role in patients with breast cancer. Qiu, H., Kong, J., Cheng, Y., et al.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05240898

NCT05240898 | A Phase 1 Study of RO7623066 Alone ... This is a Phase 1 study to assess the safety and clinical activity of RO7623066 alone and in combination in patients with advanced solid tumors.

2. genentech-clinicaltrials.com genentech-clinicaltrials.com/en/trials/cancer/solid-tumors/a-phase-1-study-of-ksq-4279-alone-and-in-combination-in-91417.html

Clinical trial for Advanced Solid Tumors-Genentech A Memb... This is a Phase 1 study to assess the safety and clinical activity of RO7623066 alone and in combination in patients with advanced solid tumors.

3. mdanderson.org mdanderson.org/newsroom/asco-novel-targeted-cancer-therapies-demonstrate-activity-safety-metastatic-solid-tumors.h00-159697545.html

ASCO: Novel targeted cancer therapies demonstrate ... Among them, 10% experienced a partial response and 42.5% achieved stable disease. With a preliminary median progression-free survival of 6.7 ...

4. clin.larvol.com clin.larvol.com/trial-detail/NCT05240898

A Phase 1 Study of RO7623066 Alone and in Combination ... The company will provide an overview of preclinical data on its first-in-class USP1 inhibitor, KSQ-4279, which supports the ongoing Phase 1 clinical trial of ...

5. forpatients.roche.com forpatients.roche.com/content/patient-platform/global/en/trials/cancer/solid-tumors/a-phase-1-study-of-ksq-4279-alone-and-in-combination-in-91417.pdf

A Phase 1 Study of KSQ-4279 Alone and in Combination in ... Trial Summary: This is a Phase 1 study to assess the safety and clinical activity of RO7623066 alone and in combination in patients with advanced solid tumors.

6. aacrjournals.org aacrjournals.org/cancerres/article/84/20/3419/749072/The-USP1-Inhibitor-KSQ-4279-Overcomes-PARP

The USP1 Inhibitor KSQ-4279 Overcomes PARP Inhibitor ... KSQ-4279 is a potent and selective inhibitor of USP1 that induces regression of PARP inhibitor–resistant tumors when dosed in combination ...

7. ksqtx.com ksqtx.com/press-releases/ksq-therapeutics-announces-first-patient-dosed-in-phase-1-study-of-ksq-4279-a-first-in-class-usp1-inhibitor-in-patients-with-advanced-solid-tumors/

KSQ Therapeutics Announces First Patient Dosed in Phase ... Preclinical safety data indicate that KSQ-4279 is well-tolerated. KSQ-4279 induces cell cycle arrest and DNA damage leading to apoptosis and ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.3005

First-in-human phase I trial of the oral first-in-class ubiquitin ... Conclusions: KSQi is a first-in-class USP1 inhibitor with an acceptable safety profile as SA and in combination. An MTD was not reached in any ...