Ovarian Cancer Clinical Trial
IACS-6274 With or Without Pembrolizumab for the Treatment of Advanced Solid Tumors
This phase I trial tests the safety, side effects, and best dose of IACS-6274 with or without pembrolizumab in treating patients with solid tumors that have spread to other places in the body (advanced). IACS-6274 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving IACS-6274 with or without pembrolizumab may help to control the disease.
To assess the safety and tolerability of oral IACS-6274 as monotherapy (Part A) and in combination with bevacizumab and weekly paclitaxel (Part B).
For Dose Escalation Only:
• To determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of IACS-6274 and in combination with bevacizumab and weekly paclitaxel (Part B).
To assess the preliminary antitumor activity of IACS-6274 as monotherapy (Part A) and in combination with bevacizumab and weekly paclitaxel (Part B) in patients with or without biomarker selected tumor types.
To characterize the PK profile of IACS-6274 as a monotherapy (Part A) and in combination with bevacizumab and weekly paclitaxel (Part B).
To evaluate predictive biomarkers of response and correlate with clinical outcome.
• 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 bevacizumab and paclitaxel intravenously (IV). 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.
Provision of written informed consent prior to any study related procedures and compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
Male or female 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.
Histologically or cytologically confirmed advanced solid tumors, specifically:
Dose Escalation for Part A may include:
Patients with tumors harboring actionable KEAP1/NFE2L2/STK11/NF1 mutations
Patients with low ASNS expression levels (HGSOC or endometrial cancer)
Patients who had immunotherapy (IO) melanoma (Minimum treatment duration of prior PD-1 or PD-L1-containing regimen of 12 weeks [or equivalent of 2 response evaluations]).
Patients with post-platinum HNSCC
Patients with chondrosarcoma
Patients with ARID1A mutant clear cell ovarian cancer
Dose Escalation for Part B may include:
- Confirmed recurrent high-grade non-mucinous ovarian cancer that is platinum-resistant, defined as disease relapse within a platinum-free interval (PFI, or the time elapsed from the last date of platinum dose until PD) of < 6 months
Dose Expansion for Part B will be limited to:
- Confirmed recurrent high-grade non-mucinous ovarian cancer with low ASNS expression levels that is platinum-resistant, defined as disease relapse within a PFI of < 6 months, and with less than 5 prior therapies.
Note: all biomarker mutations/expression levels must be confirmed prior to study treatment.
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.
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 AEs (excluding alopecia and peripheral neuropathy) have either returned to ≤Grade 1 or stabilized.
Fresh and/or archival tumor tissue from a biopsy obtained between the completion of the most recent line of treatment until study entry must be available for mutation and biomarker analysis. If available, archival tumor tissue from the time of initial diagnosis or the most recent biopsy (archival and/or fresh) will be collected. For ovarian cancer patients, a fresh biopsy must be collected in addition to archival tumor tissue. NOTE: No fresh tumor tissue will be required if a previous biopsy detected the selected mutations for each cohort. In all cases, procedures to obtain fresh tumor tissue should not put the patient at undue risk, and should only be performed if the risk is minimal (no greater than 2% risk of serious or severe complications).
Patients must have at least 1 lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by CT or MRI and is suitable for repeated assessments.
Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing.
Adequate organ function as indicated by the following laboratory values:
Absolute neutrophil count (ANC) ≥1.0×109/L
Hemoglobin ≥9.0 g/dL (>5.59 mmol/L)
Creatinine clearance (CrCl) >50 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/m2 when the lean body weight should be used, and without the need for chronic dialysis therapy).
Serum total bilirubin ≤1.5×ULN (with the exception of patients with known Gilbert's syndrome: serum total bilirubin must be <3×ULN in these patients)
Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) and alanine aminotransferase (serum glutamic pyruvic transaminase) ≤2.5×ULN or ≤5×ULN for patients with liver metastases)
Adequate cardiac function with a left ventricular ejection fraction ≥50%
Female patients of non childbearing potential, who are physiologically incapable of becoming pregnant, are eligible to enter and participate in the study if they:
have had a hysterectomy, OR
have had a bilateral oophorectomy, OR
have had a bilateral salpingectomy, OR
is postmenopausal (total cessation of menses for ≥2 years, or follicle stimulating hormone ≥50 IU/L).
Female patients of childbearing potential, who are not post-menopausal or surgically sterile and intent to be sexually active with a non-sterile male partner, are required to use one form of highly effective contraception combined with a barrier method (male condom, female condom, cervical cap, diaphragm with spermicide, or contraceptive sponge with spermicide) of contraception starting before entering the study and until 4 weeks after the last dose of treatment.
Highly effective non-hormonal contraceptive methods that are acceptable include:
Total/true abstinence*** for the total duration of the study treatment and for at least 1 month after the last dose of study treatment. Periodic abstinence using methods such as calendar ovulation, symptothermal, post ovulation methods, declaration of abstinence solely for the duration of a trial, or withdrawal are not acceptable methods of contraception.
Having a vasectomized sexual partner, who received post-vasectomy confirmation of azoospermia, combined with a barrier method as described above.
Bilateral tubal occlusion combined with a barrier method as described above.
Intrauterine device with copper banded coils, combined with a barrier method as described above.
Highly effective hormonal contraceptive methods that are acceptable include:
Combined oral pill contraception (normal and low-dose oral pills, or progesterone-based oral pills using desogestrel) combined with a barrier method as described above. NOTE: cerazette is currently the only highly efficacious progesterone-based pill available.
Injection (e.g., medroxyprogesterone) combined with a barrier method as described above.
Patch (e.g., norelgestromin or ethinyl estradiol transdermal system) combined with a barrier method as described above.
Implants (etonorgestrel-releasing) combined with a barrier method as described above.
Intravaginal device (e.g., ethinyl estradiol- or etonogestrel-releasing) combined with a barrier method as described above.
Intrauterine system (levonorgestrel-releasing) combined with a barrier method as described above.
In addition to the to use one form of highly effective contraception combined with a barrier method, female patients of childbearing potential must have a negative serum pregnancy test at screening (within 7 days of the start of treatment) and must not be breastfeeding.
Non-sterile men, who are not sexually abstinent and intend to be sexually active with a women of childbearing potential, must use a condom from the start of the trial and until 16 weeks after the last dose of treatment, or must practice total abstinence*** for the total duration of the study treatment and at least 3 months after the last dose of study treatment. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Female partners of childbearing potential should consider the use of at least one contraception method describe above. If the female partner is pregnant, male participants should use a condom plus spermicide.
Total/true abstinence is defined as a patient who refrains from any form of sexual intercourse, and this is in line with their usual and/or preferred lifestyle.
Note: Participants should not donate blood or blood components while participating in this study and through 3 months after the last dose of study intervention.
General Exclusion Criteria for All Parts
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.
Known primary central malignancy or symptomatic central nervous system metastasis(es).
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.
Uncontrolled, significant intercurrent or recent illness including, but not limited to, the following cardiac conditions:
Any unstable cardiac arrhythmia within 6 months prior to enrolment
Prolongation of the Fridericia corrected QT (QTcF) interval defined as >450 ms for males and >470 ms for females
History of any of the following cardiovascular conditions within 6 months of enrolment:
cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery
bypass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the New York Heart Association.
Major surgical intervention within 28 days before study drug administration, or an anticipated need for major surgery during the study.
Significant acute or chronic infections.
Any psychiatric condition that would prohibit the understanding or rendering of informed consent.
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.
Treatment with strong CYP450 subtype 2D6 (CYP2D6) inhibitors within 7 days of the first dose of study drug.
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.
Underlying medical conditions (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension, renal transplant and active bleeding diseases), for which in the investigator's opinion will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or AEs.
History of allergic reactions attributed to compounds of similar chemical or biological composition to any of the compounds in the study.
Known history of alcohol or drug abuse.
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 (such as refractory nausea and vomiting, chronic gastrointestinal disease or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretionof IACS-6274 and capivasertib, which are oral agents.
Patients unwilling to comply with protocol requirements related to the assigned part.
Any other disease, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent.
Part B (Dose Escalation and Dose Expansion) Specific Exclusion Criteria:
(B1) Known severe hypersensitivity reactions to monoclonal antibodies, any history of anaphylaxis, or uncontrolled asthma (that is, three or more features of partially controlled asthma).
(B2) Patient has a known hypersensitivity to paclitaxel or bevacizumab components or excipients.
(B3) Patient has a history of bowel obstruction, including sub-occlusive disease, related to the underlying disease and history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscesses. Evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction.
(B4) Patient has proteinuria as demonstrated by urine protein:creatinine ratio ≥1.0 at screening or urine dipstick for proteinuria ≥2 (patients discovered to have ≥2 proteinuria on dipstick at baseline should undergo 24-hour urine collection and must demonstrate <2 g of protein in 24 hours to be eligible).
(B5) Patient is at increased bleeding risk due to concurrent conditions (e.g., major injuries or surgery within the past 28 days prior to start of study treatment, history of hemorrhagic stroke, transient ischemic attack, subarachnoid hemorrhage, or clinically significant hemorrhage within the past 3 months).
(B6) Patient has clinically significant cardiovascular disease (e.g., significant cardiac conduction abnormalities, uncontrolled hypertension, myocardial infarction, cardiac arrhythmia or unstable angina, New York Heart Association Grade 2 or greater congestive heart failure, serious cardiac arrhythmia requiring medication, Grade 2 or greater peripheral vascular disease, and history of cerebrovascular accident [CVA]) within 6 months of enrollment. (B7) Patient has pre-existing peripheral neuropathy that is Grade ≥2 by Common Terminology Criteria for Adverse Events (CTCAE) version 4 criteria.
(B8) Patient requires paracentesis 2 weeks prior to trial enrolment
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