Recruitment

Recruitment Status
Recruiting

Inclusion Criteria

Post-immunotherapy (IO) melanoma (minimum treatment duration of prior PD-1 or PD-L1-containing regimen is 12 weeks [or equivalent of 2 response evaluations])
Serum total bilirubin =< 1.5 x ULN (with the exception of patients with known Gilbert's syndrome: serum total bilirubin must be < 3 x ULN in these patients)
Has had a bilateral oophorectomy, OR
...
Post-immunotherapy (IO) melanoma (minimum treatment duration of prior PD-1 or PD-L1-containing regimen is 12 weeks [or equivalent of 2 response evaluations])
Serum total bilirubin =< 1.5 x ULN (with the exception of patients with known Gilbert's syndrome: serum total bilirubin must be < 3 x ULN in these patients)
Has had a bilateral oophorectomy, OR
Patients must have received at least one line of therapy for advanced stage disease and be refractory or ineligible to available existing therapy(ies) known to provide clinical benefit for their condition
Left ventricular ejection fraction >= 50%
Has had a bilateral salpingectomy, OR
Patients with chondrosarcoma
Male partner has had a vasectomy
Is postmenopausal (total cessation of menses for >= 2 years, or follicle-stimulating hormone >= 50 IU/L)
Progestogen-only hormonal contraception associated with inhibition of ovulation (for example oral, implantable, injectable)
Patients with low ASNS expression levels (high-grade serous ovarian carcinoma [HGSOC] or endometrial cancer)
Male patients are eligible to enter and participate in the study if they agree to use effective methods of contraception during the study treatment period and for at least 90 days after the last dose of investigational product
Absolute neutrophil count (ANC) >= 1500/mL
Platelets >= 100,000/mL
Patients with tumors with actionable KEAP1/NFE2L2/STK11/NF1 mutations
Serum creatinine =< 1.5 x upper limit of normal (ULN) and/or creatinine clearance > 40 mL/min. Actual body weight should be used for calculating creatinine clearance using the Cockroft-Gault equation (except for patients with body mass index > 30 kg/m^2 when the lean body weight should be used)
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (for example oral, intravaginal, transdermal)
Intrauterine device
Bilateral tubal occlusion
Patients with post-platinum HNSCC
Patients with ARID1A mutant clear cell ovarian cancer Note: all biomarker mutations/expression levels must be confirmed prior to study treatment
Eastern Cooperative Oncology Group (ECOG) performance status =< 1
Intrauterine hormone-releasing system
Patients >= 18 years of age at the time of study entry who agree to participate by giving written informed consent prior to participation in any study related activities
Has had a hysterectomy, OR
Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) and alanine aminotransferase (serum glutamic pyruvic transaminase) =< 2.5 x ULN or =< 5 x ULN for patients with liver metastases)
Fresh and/or archival tumor tissue from the biopsy obtained between the completion of the most recent line of treatment until study entry must be available for mutation and biomarker analysis. Patients should not be put at undue risk to obtain fresh tumor biopsy. If available, archival tumor tissue from time of initial diagnosis will be collected in addition to the most recent biopsy (archival and/or fresh)
Measurable or non-measurable evaluable disease as defined per the Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 (or immune-related RECIST [iRECIST] for Part B only)
Hemoglobin >= 9 g/dL
Provision of written informed consent prior to any study related procedures
Prior treatment with chemotherapy, radiotherapy, immunotherapy or any investigational therapies must have been completed at least 3 weeks or at least five half-lives, whichever is shorter, before the study drug administration, and all adverse events (AEs) (excluding alopecia and peripheral neuropathy) have either returned to =< grade 1 or stabilized

Exclusion Criteria

Radiotherapy within 4 weeks prior to the start of study drug. Palliative radiotherapy for symptomatic control is acceptable if completed at least 2 weeks prior to study drug administration and no additional radiotherapy for the same lesion is planned
Known severe hypersensitivity reactions to monoclonal antibodies, any history of anaphylaxis, or uncontrolled asthma (that is, three or more features of partially controlled asthma)
Prior organ transplantation, including allogeneic stem cell transplantation
...
Radiotherapy within 4 weeks prior to the start of study drug. Palliative radiotherapy for symptomatic control is acceptable if completed at least 2 weeks prior to study drug administration and no additional radiotherapy for the same lesion is planned
Known severe hypersensitivity reactions to monoclonal antibodies, any history of anaphylaxis, or uncontrolled asthma (that is, three or more features of partially controlled asthma)
Prior organ transplantation, including allogeneic stem cell transplantation
Prior malignancy within the previous 2 years except for locally curable cancers that have been cured, such as basal or squamous cell skin cancer, or carcinoma in situ of the cervix, breast or bladder
Treatment with strong CYP450 subtype 2D6 (CYP2D6) inhibitors within 7 days of the first dose of study drug
Legal incapacity or limited legal capacity
Inability to swallow oral medications (capsules and tablets) without chewing, breaking, crushing, opening or otherwise altering the product formulation. Patients should not have gastrointestinal illnesses that would preclude the absorption of IACS-6274, which is an oral agent
Any psychiatric condition that would prohibit the understanding or rendering of informed consent
History of allergic reactions attributed to compounds of similar chemical or biological composition to any of the compounds in the study
Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 2 weeks of the first dose of study drug
Autoimmune disease that might deteriorate when receiving an immune-stimulatory agent, or immunodeficiencies
Significant acute or chronic infections
Note: Patients with stable, previously treated brain metastases may participate if neurologic symptoms have resolved, patients have been off steroids for at least 7 days, and there is no evidence of disease progression by imaging for at least 2 weeks before the first dose of study treatment
Known alcohol or drug abuse
Major surgical intervention within 28 days before study drug administration
Bypass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the New York Heart Association
Patient has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
Patients unwilling to comply with protocol requirements related to the assigned part
Underlying medical conditions that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or AEs
Cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery
Prolongation of the Fridericia corrected QT (QTcF) interval defined as > 450 ms for males and > 470 ms for females
PART B (DOSE ESCALATION AND DOSE EXPANSION) SPECIFIC EXCLUSION CRITERIA
Any unstable cardiac arrhythmia within 6 months prior to enrolment
Treatment with strong cytochrome P450 (CYP450) subtype 3A4 (CYP3A4) inducers (including St John's wort) and inhibitors (including grapefruit juice) within 7 days of the first dose of study drug

Summary

Conditions
  • Pathologic Stage IIIC Cutaneous Melanoma AJCC v8
  • Advanced Malignant Solid Neoplasm
  • Advanced Endometrial Carcinoma
  • Stage IIIC Ovarian Cancer AJCC v8
  • Pathologic Stage IIID Cutaneous Melanoma AJCC v8
  • Stage IV Uterine Corpus Cancer AJCC v8
  • Stage III Uterine Corpus Cancer AJCC v8
  • Advanced Head and Neck Squamous Cell Carcinoma
  • Advanced Melanoma
  • Stage IVB Ovarian Cancer AJCC v8
  • Refractory High Grade Ovarian Serous Adenocarcinoma
  • Stage IVB Uterine Corpus Cancer AJCC v8
  • Advanced Ovarian Clear Cell Adenocarcinoma
  • Chondrosarcoma
  • Clinical Stage III Cutaneous Melanoma AJCC v8
  • Refractory Melanoma
  • Clinical Stage IV Cutaneous Melanoma AJCC v8
  • Stage III Ovarian Cancer AJCC v8
  • Refractory Head and Neck Squamous Cell Carcinoma
  • Stage IIIC Uterine Corpus Cancer AJCC v8
  • Pathologic Stage III Cutaneous Melanoma AJCC v8
  • Stage IIIB Uterine Corpus Cancer AJCC v8
  • Stage IVA Uterine Corpus Cancer AJCC v8
  • Stage IV Ovarian Cancer AJCC v8
  • Stage IIIA Uterine Corpus Cancer AJCC v8
  • Stage IIIC2 Uterine Corpus Cancer AJCC v8
  • Stage IVA Ovarian Cancer AJCC v8
  • Refractory Ovarian Clear Cell Adenocarcinoma
  • Stage IIIA1 Ovarian Cancer AJCC v8
  • Stage IIIB Ovarian Cancer AJCC v8
  • Refractory Endometrial Carcinoma
  • Pathologic Stage IIIA Cutaneous Melanoma AJCC v8
  • Pathologic Stage IIIB Cutaneous Melanoma AJCC v8
  • Stage IIIA2 Ovarian Cancer AJCC v8
  • Stage IIIC1 Uterine Corpus Cancer AJCC v8
  • Pathologic Stage IV Cutaneous Melanoma AJCC v8
  • Stage IIIA Ovarian Cancer AJCC v8
Type
Interventional
Phase
Phase 1
Design
  • Allocation: Non-Randomized
  • Intervention Model: Parallel Assignment
  • Masking: None (Open Label)
  • Primary Purpose: Treatment

Participation Requirements

Age
Between 18 years and 125 years
Gender
Both males and females

Description

PRIMARY OBJECTIVES: I. To assess the safety and tolerability of oral glutaminase inhibitor IPN60090 (IACS-6274) as monotherapy (Part A) and in combination therapy with pembrolizumab (Part B). II. To determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of IACS-6274 in co...

PRIMARY OBJECTIVES: I. To assess the safety and tolerability of oral glutaminase inhibitor IPN60090 (IACS-6274) as monotherapy (Part A) and in combination therapy with pembrolizumab (Part B). II. To determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of IACS-6274 in combination therapy with pembrolizumab (Part B). (For Dose Escalation Only) SECONDARY OBJECTIVES: I. To assess the preliminary antitumor activity of IACS-6274 as monotherapy (Part A) and in combination with pembrolizumab (Part B) in patients with or without biomarker selected tumor types. II. To characterize the pharmacokinetics (PK) and pharmacodynamic (PD) profile of IACS-6274 as a monotherapy (Part A) and in combination with pembrolizumab (Part B). III. To evaluate biomarkers of patient stratification and correlate them with clinical outcome. EXPLORATORY OBJECTIVE: I. To collect biobank samples for potential future analysis of biomarkers (optional, informed consent required). OUTLINE: This is a dose-escalation study of IACS-6274 followed by a dose-expansion study. Patients are assigned to 1 of 2 parts. PART A: Patients receive IACS-6274 orally (PO) twice daily (BID) on days 1-21. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. PART B: Patients receive IACS-6274 PO BID on days 1-21 and pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days. Part B patients are also followed up at 60 and 90 days.

Inclusion Criteria

Post-immunotherapy (IO) melanoma (minimum treatment duration of prior PD-1 or PD-L1-containing regimen is 12 weeks [or equivalent of 2 response evaluations])
Serum total bilirubin =< 1.5 x ULN (with the exception of patients with known Gilbert's syndrome: serum total bilirubin must be < 3 x ULN in these patients)
Has had a bilateral oophorectomy, OR
...
Post-immunotherapy (IO) melanoma (minimum treatment duration of prior PD-1 or PD-L1-containing regimen is 12 weeks [or equivalent of 2 response evaluations])
Serum total bilirubin =< 1.5 x ULN (with the exception of patients with known Gilbert's syndrome: serum total bilirubin must be < 3 x ULN in these patients)
Has had a bilateral oophorectomy, OR
Patients must have received at least one line of therapy for advanced stage disease and be refractory or ineligible to available existing therapy(ies) known to provide clinical benefit for their condition
Left ventricular ejection fraction >= 50%
Has had a bilateral salpingectomy, OR
Patients with chondrosarcoma
Male partner has had a vasectomy
Is postmenopausal (total cessation of menses for >= 2 years, or follicle-stimulating hormone >= 50 IU/L)
Progestogen-only hormonal contraception associated with inhibition of ovulation (for example oral, implantable, injectable)
Patients with low ASNS expression levels (high-grade serous ovarian carcinoma [HGSOC] or endometrial cancer)
Male patients are eligible to enter and participate in the study if they agree to use effective methods of contraception during the study treatment period and for at least 90 days after the last dose of investigational product
Absolute neutrophil count (ANC) >= 1500/mL
Platelets >= 100,000/mL
Patients with tumors with actionable KEAP1/NFE2L2/STK11/NF1 mutations
Serum creatinine =< 1.5 x upper limit of normal (ULN) and/or creatinine clearance > 40 mL/min. Actual body weight should be used for calculating creatinine clearance using the Cockroft-Gault equation (except for patients with body mass index > 30 kg/m^2 when the lean body weight should be used)
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (for example oral, intravaginal, transdermal)
Intrauterine device
Bilateral tubal occlusion
Patients with post-platinum HNSCC
Patients with ARID1A mutant clear cell ovarian cancer Note: all biomarker mutations/expression levels must be confirmed prior to study treatment
Eastern Cooperative Oncology Group (ECOG) performance status =< 1
Intrauterine hormone-releasing system
Patients >= 18 years of age at the time of study entry who agree to participate by giving written informed consent prior to participation in any study related activities
Has had a hysterectomy, OR
Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) and alanine aminotransferase (serum glutamic pyruvic transaminase) =< 2.5 x ULN or =< 5 x ULN for patients with liver metastases)
Fresh and/or archival tumor tissue from the biopsy obtained between the completion of the most recent line of treatment until study entry must be available for mutation and biomarker analysis. Patients should not be put at undue risk to obtain fresh tumor biopsy. If available, archival tumor tissue from time of initial diagnosis will be collected in addition to the most recent biopsy (archival and/or fresh)
Measurable or non-measurable evaluable disease as defined per the Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 (or immune-related RECIST [iRECIST] for Part B only)
Hemoglobin >= 9 g/dL
Provision of written informed consent prior to any study related procedures
Prior treatment with chemotherapy, radiotherapy, immunotherapy or any investigational therapies must have been completed at least 3 weeks or at least five half-lives, whichever is shorter, before the study drug administration, and all adverse events (AEs) (excluding alopecia and peripheral neuropathy) have either returned to =< grade 1 or stabilized

Exclusion Criteria

Radiotherapy within 4 weeks prior to the start of study drug. Palliative radiotherapy for symptomatic control is acceptable if completed at least 2 weeks prior to study drug administration and no additional radiotherapy for the same lesion is planned
Known severe hypersensitivity reactions to monoclonal antibodies, any history of anaphylaxis, or uncontrolled asthma (that is, three or more features of partially controlled asthma)
Prior organ transplantation, including allogeneic stem cell transplantation
...
Radiotherapy within 4 weeks prior to the start of study drug. Palliative radiotherapy for symptomatic control is acceptable if completed at least 2 weeks prior to study drug administration and no additional radiotherapy for the same lesion is planned
Known severe hypersensitivity reactions to monoclonal antibodies, any history of anaphylaxis, or uncontrolled asthma (that is, three or more features of partially controlled asthma)
Prior organ transplantation, including allogeneic stem cell transplantation
Prior malignancy within the previous 2 years except for locally curable cancers that have been cured, such as basal or squamous cell skin cancer, or carcinoma in situ of the cervix, breast or bladder
Treatment with strong CYP450 subtype 2D6 (CYP2D6) inhibitors within 7 days of the first dose of study drug
Legal incapacity or limited legal capacity
Inability to swallow oral medications (capsules and tablets) without chewing, breaking, crushing, opening or otherwise altering the product formulation. Patients should not have gastrointestinal illnesses that would preclude the absorption of IACS-6274, which is an oral agent
Any psychiatric condition that would prohibit the understanding or rendering of informed consent
History of allergic reactions attributed to compounds of similar chemical or biological composition to any of the compounds in the study
Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 2 weeks of the first dose of study drug
Autoimmune disease that might deteriorate when receiving an immune-stimulatory agent, or immunodeficiencies
Significant acute or chronic infections
Note: Patients with stable, previously treated brain metastases may participate if neurologic symptoms have resolved, patients have been off steroids for at least 7 days, and there is no evidence of disease progression by imaging for at least 2 weeks before the first dose of study treatment
Known alcohol or drug abuse
Major surgical intervention within 28 days before study drug administration
Bypass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the New York Heart Association
Patient has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
Patients unwilling to comply with protocol requirements related to the assigned part
Underlying medical conditions that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or AEs
Cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery
Prolongation of the Fridericia corrected QT (QTcF) interval defined as > 450 ms for males and > 470 ms for females
PART B (DOSE ESCALATION AND DOSE EXPANSION) SPECIFIC EXCLUSION CRITERIA
Any unstable cardiac arrhythmia within 6 months prior to enrolment
Treatment with strong cytochrome P450 (CYP450) subtype 3A4 (CYP3A4) inducers (including St John's wort) and inhibitors (including grapefruit juice) within 7 days of the first dose of study drug

Locations

Houston, Texas, 77030
Houston, Texas, 77030

Tracking Information

NCT #
NCT05039801
Investigators
Timothy A Yap M.D. Anderson Cancer Center