IRB Study Number 24-274
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
To evaluate the safety and tolerability of vorasidenib when administered in combination with pembrolizumab and determine the recommended combination dose (RCD) of vorasidenib with pembrolizumab.
To evaluate CD3+ T-cell infiltration in tumors following pre-surgical treatment with vorasidenib in combination with pembrolizumab compared to untreated control tumors
To assess preliminary clinical activity of vorasidenib in combination with pembrolizumab using Modified Response Assessment in Neuro-oncology (mRANO) criteria.
Secondary Objectives
To assess overall survival (OS).
To characterize the pharmacokinetics of vorasidenib in blood and tumor when administered alone and in combination
To evaluate the 2-hydroxygluarate (2-HG) concentration in resected tumors following pre-surgical treatment with vorasidenib in combination with pembrolizumab or vorasidenib alone compared to untreated control tumors.
To evaluate the 2-hydroxygluarate (2-HG) concentration in resected tumors following pre-surgical treatment with vorasidenib in combination with pembrolizumab or vorasidenib alone compared to untreated control tumors.
Inclusion Criteria
Demographic Characteristics
- Be ≥ 18 years of age.
General Criteria
Have Karnofsky Performance Status (KPS; see Appendix 2) of ≥ 70%.
Have expected survival of ≥ 3 months.
Informed Consent
- Is able to understand and provides written informed consent for the trial prior to any study-specific procedures as described in Section 4.1, and is willing to comply with scheduled visits, treatment plans, procedures, and laboratory tests, including serial peripheral blood sampling and urine sampling, during the study. A legally authorized representative may consent on behalf of a subject who is otherwise unable to provide informed consent, if acceptable to and approved by the site and/or site’s IRB/IEC.
Medical and Therapeutic Criteria
Have histologically confirmed Grade 2 or Grade 3 astrocytoma (per the 2016 or 2021 WHO Classification of Tumors of the central nervous system)
Have:
a. Documented IDH1-R132H gene mutation and;
b. Absence of 1p19q co-deletion (i.e., non-co-deleted, or intact) and/or documented loss of nuclear ATRX expression or ATRX mutation by local testing.
Have measurable, MRI-evaluable, unequivocal contrast enhancing disease as determined by institution radiologist/Investigator at Screening on either 2D T1 post-contrast weighted images or 3D T1 post-contrast weighted images. Per mRANO criteria, measurable lesion is defined as at least 1 enhancing lesion measuring ≥ 1 cm x ≥ 1 cm.
Have recurrent or progressive disease and received prior treatment with chemotherapy, radiation, or both.
Surgical resection is indicated for treatment, but surgery is not urgently indicated (e.g., for whom surgery within the next 6-9 weeks is appropriate). (NOTE: This criterion only applies to subjects enrolled in the perioperative phase of the study. Subjects in the Safety Lead-in should not require surgery).
Have adequate bone marrow function as evidenced by the following criteria:
a. Absolute neutrophil count ≥ 1500/mm3 or 1.5 ×109/L;
b. Hemoglobin ≥ 9 g/dL (Criteria must be met at Screening without packed red blood cell (pRBC) transfusion within the prior 2 weeks. Subjects can be on stable dose of erythropoietin (≥ approximately 3 months) (See Appendix 6) and
c. Platelets ≥ 100 × 103/mm3 or 100 × 109/L.
- Have adequate hepatic function as evidenced by the following criteria:
a. Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) at or below normal limits. An elevation ≤1.5 × ULN and considered not clinically significant by the Investigator may be allowed following Medical Monitor approval; and
c. Alkaline phosphatase ≤ 2.5 × ULN.
Have adequate renal function as evidenced by: Creatinine clearance >40 mL/min based on the Cockcroft Gault glomerular filtration rate estimation: (140 – Age) × (Weight in kg) × (0.85 if female) / 72 × Serum Creatinine.
Women of childbearing potential (WOCBP) must have a negative serum pregnancy test before the start of therapy. WOCBP are defined as having had onset of their first menstrual period and have not undergone a hysterectomy or bilateral oophorectomy or are not naturally post-menopausal (i.e., have not menstruated at all in the preceding 24 consecutive months).
Sex and Contraceptive/Barrier Requirements
- WOCBP must agree to abstain from sexual intercourse or to use 2 highly effective forms of contraception, at least one of which must be a barrier method, from the time of giving informed consent throughout the study, and for 120 days after the last dose of study treatment. Vorasidenib and pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if pembrolizumab has transient adverse effects on the composition of sperm. Subjects should be informed that taking the study medication may involve unknown risks to the fetus (unborn baby) if pregnancy were to occur during the study.
Male subjects with WOCBP partners must use a condom during the study and until at least 120 days after the last dose of study treatment. In addition, contraception should be considered for their female partners. Contraceptive measures do not apply if the subject is sterile, vasectomized or sexually abstinent. Sperm donation from male subjects will not be allowed during the study and for 120 days after the last dose of study treatment.
A female is eligible to participate in the trial if she is not a WOCBP or a WOCBP who agrees to follow contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment. In order to participate in the study, subjects of childbearing potential must adhere to the contraception requirement from the giving of informed consent throughout the study period up to at least 120 days after the last dose of study treatment.
Abstinence is acceptable only as true abstinence when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods) and withdrawal are not acceptable methods of contraception. Highly effective forms of contraception are defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, intrauterine hormone release systems, bilateral tubal ligation, condoms with spermicide, or male partner sterilization. Please refer to Appendix 5 for further contraception considerations.
If there is any question that a subject of childbearing potential will not reliably comply with the requirements for contraception, that subject should not be entered into the study.
Exclusion Criteria
General Criteria
Unable to swallow oral medication.
Are pregnant or breastfeeding. It is unknown whether vorasidenib or pembrolizumab is excreted in human milk. Since many drugs are excreted in human milk, and because of the potential for serious adverse reactions in the nursing infant, subjects who are breastfeeding are not eligible for enrollment.
Is unlikely to cooperate in the study.
Is participating in another interventional study at the same time; participation in non-interventional registries or epidemiological studies is allowed.
Subject previously signed informed consent and was enrolled into this study.
Medical and Therapeutic Criteria
Have received prior systemic anti-cancer therapy within 1 month of the first dose of IMP, radiation within 12 months of the first dose of IMP, or an investigational agent < 14 days prior to the first dose of IMP. In addition, the first dose of IMP should not occur before a period of ≥ 5 half-lives of the investigational agent has elapsed.
Have received 2 or more courses of radiation.
Subjects who have not recovered from toxicity of previous anti-cancer therapy, including Grade ≥ 2 non-hematologic toxicity, according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) v 5.0, prior to the first IMP administration. Certain toxicities will not be considered in this category (e.g. alopecia, peripheral neuropathy, weakness, memory loss, etc).
Have received any prior treatment with an IDH inhibitor; anti-PD1, anti-PD-L1, or anti-PD-L2 agent, or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137); any other checkpoint inhibitor; bevacizumab; or any prior vaccine therapy.
Have received a live or live attenuated vaccine within 30 days prior to the first dose of IMP. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, seasonal flu, H1N1 flu, rabies, Bacillus Calmette-Guerin (BCG), and oral typhoid vaccine. Season influenza vaccines that are intranasal vaccines (e.g. FluMist®) are live attenuated vaccines and are not allowed within 30 days prior to the first dose of IMP; however, influenza vaccines that are killed virus vaccines are allowed. The Coronavirus Disease 2019 (COVID-19) vaccine and booster shot are permitted.
Are taking therapeutic doses (defined as equivalent of > 1.5 mg dexamethasone or > 10 mg of prednisone or equivalent daily) of steroids. Subjects taking physiologic doses (defined as equivalent of ≤ 1.5 mg dexamethasone or ≤ 10 mg prednisone daily) for medical conditions not related to glioma will be permitted.
Require use of any other immunosuppressive medication.
Have had an allogeneic tissue/solid organ transplant
Severe or uncontrolled active acute or chronic infection, or an unexplained fever > 38.5°C within 7 days of C1D1.
Have any known hypersensitivity to any of the components of vorasidenib, pembrolizumab or any other monoclonal antibody.
Have significant active cardiac disease within 6 months before the start of study treatment, including New York Heart Association Class III or IV congestive heart failure, atrial fibrillation, myocardial infarction, unstable angina, and/or stroke.
Have left ventricular ejection fraction (LVEF) < 40% by echocardiogram (or by other methods according to institutional practice) obtained within 28 days before the start of study treatment.
Have heart rate-corrected QT interval using Fridericia’s formula (QTcF) interval of ≥ 450 msec or with other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome). Subjects with bundle branch block and a prolonged QTcF interval should be reviewed by the Medical Monitor for potential inclusion.
Medications that are substrates of CYP2C8, CYP2C9, CYP2C19 or CYP3A with a narrow therapeutic index are not allowed if the subject is receiving vorasidenib. (Subjects should be transferred to other medications before receiving the first dose of IMP.)
Have active hepatitis B (HBV) or hepatitis C (HCV) infections, known positive human immunodeficiency virus (HIV) antibody results, or AIDS-related illness. Subjects with a sustained viral response to HCV or immunity to prior HBV infection will be permitted. Subjects with chronic HBV that is adequately suppressed per institutional practice will be permitted.
Have known active inflammatory gastrointestinal disease, chronic diarrhea, previous gastric resection or lap band dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally. Gastroesophageal reflux disease under medical treatment is allowed (assuming there is no potential for drug interaction).
Have a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease or have had radiation pneumonitis.
Have leptomeningeal disease.
Have known coagulopathy.
Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. Subjects with vitiligo or resolved childhood asthma/atopy are allowed. Subjects who require intermittent use of bronchodilators or local steroid injections are allowed. Subjects with hypothyroidism that is stable on hormone replacement are also allowed.
Clinically significant thyroid disorder, except if stabilized and controlled with a treatment for at least 3 months prior to the first IMP administration.
Concurrent active malignancy except for a) curatively resected nonmelanoma skin cancer or b) curatively treated carcinoma in situ. Subjects with previously treated malignancies are eligible provided they have been disease-free for 3 years at Screening.
Have any active substance abuse disorder, or psychiatric condition including recent (within 12 months of Day 1) or active suicidal ideation or behavior that would interfere with the subject’s ability to cooperate with study participation or investigational product administration for the full duration of the study and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study.
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
For prior and prohibited concomitant medication, refer to Section 6.3.
