A Phase 1 Study of KSQ-4279 Alone and in Combination in Patients with Advanced Solid Tumors
A Phase 1 Study of KSQ-4279 Alone and in Combination in Patients with Advanced Solid Tumors
NCT #
NCT05240898
Condition(s)
Solid Tumors
Molecular Target(s)
Drug Classification(s)
Cytotoxic, Small Molecule (Targeted)
Agents(s)
KSQ-4279
Phase(s)
I
Mechanism of Action
KSQ-4279 is a potent, selective small molecule inhibitor of USP1 that is being developed for thetreatment of solid tumors.
Purpose
In this study, the sponsor and investigators want to learn:
- How much of the study drug can be given with an acceptable level of side effects alone and in combination with Olaparib or Carboplatin
- The effects of the study drug (good and bad) alone and in combination with Olaparib or Carboplatin
- How much of the study drug is absorbed into the blood and how fast it is removed
- If research tests can be used in the future to predict who will benefit from KSQ-4279 alone or in combination with Olaparib or Carboplatin
- How the study drug is acting on your body
- Life expectancy of ≥ 12 weeks
- Measurable disease or non-measurable per RECIST v1.1 in dose escalation only; patients in dose expansion are required to have measurable disease per RECIST v1.1
- Recovered to ≤ Grade 1 or baseline toxicity (except alopecia) from prior therapy (per NCI-CTCAE v5.0)
- Eastern Cooperative Oncology Group performance status 0 or 1
- Adequate bone marrow and organ function at baseline
- Female patients who are women of childbearing potential with confirmed of a negative pregnancy test and agreement to the use of a highly effective contraceptive method or at least 2 effective methods at the same time during study treatment period and for up to 3 months after the last dose of study treatment. Male patients must be willing to use effective barrier contraception during the study treatment period and for up 3 months after the last dose of study treatment.
- Histologically or cytologically confirmed locally advanced (unresectable) or metastatic solid tumors who meet one of the following criteria (dose escalation only):
- Relapsed or progressed through standard therapy
- Have a disease for which no standard effective therapy exists
- Not a candidate for standard effective therapy
- KSQ-4279 Monotherapy Tumor Biopsy cohort:
- Have a deleterious mutation (germline or somatic) in one of the following genes involved in the HRR pathway (BRCA1, BRCA2, PALB2, RAD51, RAD51B, RAD51C, RAD51D, BARD1, BRIP1, FANCA, and NBN) as assessed by a CLIA-certified or equivalent laboratory
- Have tumor tissue that is easily accessible for pre-treatment and on-treatment biopsy in the opinion of the Investigator, and be willing to undergo pre-treatment and on-treatment biopsies per protocol
- KSQ-4279 in Combination Dose Escalation KSQ-4279 + OLA:
- Have a deleterious mutation (germline or somatic) in at least 1 of the following genes involved in the HRR pathway (BRCA1, BRCA2, PALB2, RAD51, RAD51B, RAD51C, RAD51D, BARD1, BRIP1, FANCA, and NBN) as assessed by a CLIA-certified or equivalent laboratory
- Locally advanced (unresectable) or metastatic tumors for which PARPi is appropriate, or locally advanced (unresectable) or metastatic tumors that may be sensitive to PARPi (eg, ovarian cancer, TNBC, cholangiocarcinoma, prostate cancer, and pancreatic cancer)
- At least the first 2 patients per DL must have tumor tissue that is easily accessible for pretreatment and on-treatment biopsy in the opinion of the Investigator, and be willing to undergo pre-treatment and on-treatment biopsies per protocol
*KSQ-4279 + CARBO: - Have a deleterious mutation (germline or somatic) in at least 1 of the following genes involved in the HRR pathway (BRCA1, BRCA2, PALB2, RAD51, RAD51B, RAD51C, RAD51D, BARD1, BRIP1, FANCA, and NBN) as assessed by a CLIA-certified or equivalent laboratory
- Locally advanced (unresectable) or metastatic tumor for which CARBO is appropriate, or locally advanced (unresectable) or metastatic tumors that may be sensitive to CARBO (eg, non-small cell lung carcinoma (NSCLC), pancreatic cancer, cholangiocarcinoma, bladder cancer, ovarian cancer, and TNBC)
- At least the first 2 patients per DL must have tumor tissue that is easily accessible for pretreatment and on-treatment biopsy in the opinion of the Investigator and be willing to undergo pre-treatment and on-treatment biopsies per protocol
- Expansion KSQ-4279 Monotherapy Expansion HRR+ Ovarian Cancer
- Histologically diagnosed recurrent or persistent high grade serous ovarian cancer (including primary peritoneal and/or fallopian tube cancer)
- Have a deleterious mutation (germline or somatic) in at least 1 of the following genes involved in the HRR pathway (BRCA1, BRCA2, PALB2, RAD51, RAD51B, RAD51C, RAD51D, BARD1, BRIP1, FANCA, and NBN ) as assessed by a CLIA certified or equivalent laboratory
- Received prior platinum-based chemotherapy – Note: Patients may have platinum-sensitive or resistant disease HRR+ Solid Tumor
- Histologically or cytologically confirmed locally advanced (unresectable) or metastatic solid tumor (eg,TNBC, cholangiocarcinoma, endometrial carcinoma, and prostate cance)r
- Have a deleterious mutation (germline or somatic) in at least 1 of the following genes involved in the HRR pathway (BRCA1, BRCA2, PALB2, RAD51, RAD51B, RAD51C, RAD51D, BARD1, BRIP1, FANCA, and NBN) as assessed by a CLIA-certified or equivalent laboratory
- Received prior platinum-based chemotherapy – Note: Patients may have platinum-sensitive or resistant disease
- KSQ-4279 in Combination Expansion
- KSQ-4279 + OLA: HRR+ Ovarian Cancer
- Histologically diagnosed recurrent or persistent high grade serous ovarian cancer (including primary peritoneal and/or fallopian tube cancer)
- Have a deleterious mutation (germline or somatic) in at least 1 of the following genes involved in the HRR pathway (BRCA1, BRCA2, PALB2, RAD51, RAD51B, RAD51C, RAD51D, BARD1, BRIP1, FANCA, and NBN) as assessed by a CLIA-certified or equivalent laboratory
- Received prior platinum-based chemotherapy – Note: Patients may have platinum-sensitive or resistant disease
- Received prior PARPi therapy
- HRR+ Solid Tumor
- Histologically or cytologically confirmed locally advanced (unresectable) or metastatic solid tumor (eg, TNBC, cholangiocarcinoma, endometrial carcinoma, and prostate cancer)
- Have a deleterious mutation (germline or somatic) in at least 1 of the following genes involved in the HRR pathway (BRCA1, BRCA2, PALB2, RAD51, RAD51B, RAD51C, RAD51D, BARD1, BRIP1, FANCA, and NBN) as assessed by a CLIA-certified or equivalent laboratory
- Received prior platinum-based chemotherapy – Note: Patients may have platinum-sensitive or resistant disease
KSQ-4279 + CARBO: HRR+ Solid Tumor - Histologically or cytologically confirmed locally advanced (unresectable) or metastatic solid tumor (eg, NSCLC, ovarian cancer, pancreatic cancer, bladder cancer, and TNBC)
- Have a deleterious mutation (germline or somatic) in at least 1 of the following genes involved in the HRR pathway (BRCA1, BRCA2, PALB2, RAD51, RAD51B, RAD51C, RAD51D, BARD1, BRIP1, FANCA, and NBN) as assessed by a CLIA-certified or equivalent laboratory
- Received at least 1 prior platinum-based chemotherapeutic regimen for management of primary disease Note: Prior PARPi therapy is allowed
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
- Received prior platinum-based chemotherapy – Note: Patients may have platinum-sensitive or resistant disease
- Received prior PARPi therapy
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