IRB Study Number 22-907
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objective(s)
Dose escalation part:
To characterize safety and tolerability of IAG933 in patients with mesothelioma, NF2/LATS1/LATS2 mutated tumors and tumors with functional YAP/TAZ fusions and to identify the MTD(s) and/or RD(s) for expansion.
Dose expansion part:
To further evaluate the safety and tolerability of IAG933 in the expansion groups
Secondary Objective(s)
Dose escalation part:
To assess the preliminary antitumor activity of IAG933
To characterize the PK of IAG933
Dose expansion part:
To assess the antitumor activity of IAG933 in the expansion groups
To assess overall survival in the expansion group
To characterize the PK of IAG933
Reference: noveltc
Inclusion Criteria
Signed informed consent must be obtained prior to participation in the study.
Male or female patients must be ≥ 18 years of age.
Dose escalation part: patients with histologically or cytologically confirmed diagnosis of advanced (unresectable or metastatic) mesothelioma or other solid tumors. Patients with solid tumors other than mesothelioma must have local available data for loss-of-function NF2/LATS1/LATS2 genetic alterations (truncating mutation or gene deletion; LATS1/LATS2 mutations will only be included in the dose escalation part), or functional YAP/TAZ fusions (see Appendix 4 for requirements for molecular alterations). Patients with malignant EHE can be enrolled with only histological confirmation of the disease. Patients must have failed available standard therapies, be intolerant of or ineligible for standard therapy, or for whom no standard therapy exists.
Dose expansion part: the following patients will be enrolled into 3 different treatment groups:
Group 1: Advanced (unresectable or metastatic) MPM patients who have failed available standard therapies for advanced/metastatic disease, are intolerant or ineligible to receive such therapy, or for whom no standard therapy exists.
Group 2: Advanced (unresectable or metastatic) solid tumor patients with available local data for NF2 truncating mutation or deletions (refer to Appendix 4 for more details). Patient must have failed available standard therapies, be intolerant or ineligible to receive such therapy, or for whom no standard therapy exists.
Group 3: Advanced (unresectable or metastatic) solid tumor patients with available local data for functional YAP/TAZ fusions (refer to Appendix 4 for more details). EHE patients can be included with only histological confirmation of the disease. Patient must have failed available standard therapies, be intolerant or ineligible to receive such therapy, or for whom no standard therapy exists.
Group 4: Advanced (unresectable or metastatic) non-pleural mesothelioma patients who have failed available standard therapies for advanced/metastatic disease, are intolerant or ineligible to receive such therapy, or for whom no standard therapy exists.
Presence of at least one measurable lesion according to mRECIST v1.1 (for mesothelioma patients, refer to Appendix 2), RECIST v1.1 (for patients with other solid tumors, refer to Appendix 1), or RANO (for patients with primary brain tumors, refer to Appendix 3).
Patient must have a site of disease amenable to biopsy and be a candidate for tumor biopsy according to the treating institution’s guidelines. Patient must be willing to undergo a new tumor biopsy at screening/baseline, and again during therapy on this study. An archival tumor sample (preferably obtained within 3 months prior to screening and after last systemic treatment) may be used at screening. An exception to this exists for patients with primary brain/CNS tumors including meningioma, however the most recent archival tumor sample is requested from these patients if available. Other exceptions may be considered after documented discussion with Novartis. During the dose expansion part of the study, a decision may be made to stop the collection of on-treatment biopsies. This decision may be based on data collected during the study and/or strategic considerations.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Exclusion Criteria
- Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes:
a. ≤ 4 weeks for thoracic radiotherapy to lung fields or limited field radiation for palliation within ≤ 2 weeks prior to the first dose of study treatment. An exception to this exists for patients who have received palliative radiotherapy to bone, who must have recovered from radiotherapy-related toxicities but for whom a 2-week washout period is not required.
b. ≤ 4 weeks or ≤ 5 half-lives (whichever is shorter) for biological therapy (including monoclonal antibodies) or continuous or intermittent small molecule therapeutics or any other investigational agent
c. ≤3 weeks for treatment with cytotoxic agents or ≤ 6 weeks for cytotoxic agents with risk of major delayed toxicities, such as nitrosoureas and mitomycin C
d. ≤ 4 weeks for immuno-oncologic therapy, such as CTLA4, PD-1, or PD-L1 antagonists
e. Prior treatment with TEAD inhibitor at any time
For mesothelioma patients: use of non-invasive antineoplastic therapy (e.g., tumor treating fields, brand name Optune Lua™) within 2 weeks of the tumor assessment at screening.
Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study entry; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type.
Presence of symptomatic CNS metastases, or CNS tumors or metastases that require local CNS-directed therapy (such as radiotherapy within 3 months of tumor assessment at screening or surgery), or increasing doses of corticosteroids 2 weeks prior to study entry.
Patients with treated symptomatic brain tumors should be neurologically stable (for 4 weeks post-treatment and prior to study entry) and at a dose of ≤ 10 mg per day prednisone or equivalent for at least 2 weeks before administration of any study treatment.
Patients who have undergone major surgery ≤ 4 weeks prior to first dose of study treatment.
History of allogeneic bone marrow or solid organ transplant.
Insufficient renal function at Screening (patients meeting any of the following criteria):
a. Serum creatinine > 1.5 x ULN
b. Estimated glomerular filtration rate (eGFR) Dose escalation part: < 50 mL/min/1.73m2 (calculated using the CKD-EPI Creatinine-Cystatin C formula) or if cystatin C is unavailable, creatinine clearance < 50 mL/min calculated using the Cockcroft-Gault formula; Dose expansion part: < 50 mL/min/1.73m2 (calculated using the CKD-EPI Creatinine formula without cystatin C) (relevant formulas listed in Appendix 7).
c. Urine protein-creatinine ratio > 0.5 g/g (56.5 mg/mmol)
- Clinically significant cardiac disease or risk factors at screening, including any of the following:
a. Clinically significant and/or uncontrolled heart disease, including coronary artery disease, uncontrolled hypertension, clinically significant arrhythmia, and congestive heart failure (NYHA grade ≥ 2).
b. Acute myocardial infarction or unstable angina pectoris within 6 months prior to study entry.
c. Left ventricular ejection fraction (LVEF) < 50% as determined by Cardiovascular magnetic resonance imaging (cardiac magnetic resonance imaging (MRI)) or trans-thoracic echocardiography (TTE).
d. Resting QTcF ≥450 msec (male) or ≥460 msec (female) at screening, or QTc not assessable.
e. Resting heart rate (physical exam or 12 lead ECG) < 50 bpm.
f. PR interval > 200ms, Mobitz type II second degree AV block, high-grade AV block or third degree (complete) AV block.
g. Risk factors for Torsades de Pointes (TdP), including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia, or any of the following:
i. History of familial long QT syndrome, known family history of TdP or family history of idiopathic sudden death
ii. Concomitant QT prolonging medication(s) with a known risk of QT prolongation that cannot be discontinued or replaced by safe alternative medications at least 7 days prior to the start of study treatment and for the duration of the study (see Appendix 5)
- Insufficient bone marrow function at screening:
a. Absolute Neutrophil Count (ANC) < 1.5 x 109/L
b. Hemoglobin < 9.0 g/dL without transfusion support within 7 days prior to start of study treatment
c. Platelet count < 75 x 109/L without transfusion support within 7 days prior to start of study treatment
- Insufficient hepatic function at screening:
a. Serum total bilirubin > 1.5 x upper limit of normal (ULN) (An exception is for patients with Gilbert’s syndrome, who are excluded if total bilirubin > 3.0 x ULN) and direct bilirubin > 1.5 x ULN.
b. Aspartate aminotransferase (AST) > 3 x ULN or > 5 x ULN if liver metastases are present.
c. Alanine aminotransferase (ALT) > 3 x ULN or > 5 x ULN if liver metastases are present.
- Patients who have the following laboratory values > Common Terminology Criteria for Adverse Events (CTCAE) grade 1 (treatment may be given during screening to correct values):
a. Potassium
b. Magnesium
c. Total calcium (corrected for low serum albumin)
- Active hepatitis B or C infection.
a. Active hepatitis B is defined by positive HBsAg and detectable HBV DNA level in serum by PCR-based method. Patients with serologic evidence of chronic HBV infection but have an HBV viral load below the limit of quantification can be enrolled with concurrent viral suppressive therapy.
b. Active hepatitis C is defined by quantitative HCV RNA results greater than the lower limits of detection of the assay. Refer to Table 8-7 for expected testing.
Known history of testing positive for Human Immunodeficiency Virus (HIV) infections. For countries where known HIV status is mandatory: test HIV status during screening using a local test.
Known active COVID-19 infection.
Use of any live vaccines against infectious diseases within 4 weeks or initiation of study treatment.
Inability to take an orally administered drug, or presence of medical disorder or prior surgical resection that may affect the absorption of the study drug.
Patient receiving medications or herbs that are known to be strong and moderate CYP3A4 inhibitors and strong CYP3A4 inducers, which cannot be discontinued 7 days prior to the start of study treatment and for the duration of the study (Appendix 5).
Patients participating in any additional parallel investigational drug or medical device studies.
Patients who have not had resolution, except where otherwise stated in the inclusion/ exclusion criteria, of all clinically significant toxic effects of prior systemic cancer therapy, surgery, or radiotherapy to Grade ≤ 2, except for alopecia, vitiligo, residual hypothyroidism requiring only hormone replacement or other endocrinopathies adequately treated with replacement therapy, or peripheral neuropathy and ototoxicity (which are excluded if ≥ Common Terminology Criteria for Adverse Events (CTCAE) grade 3)
Any medical condition that would, in the Investigator’s judgment, prevent the patient’s participation in the clinical study due to safety concerns or compliance with clinical study procedures.
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant from menarche until becoming post-menopausal, unless they are using highly effective methods of contraception (failure rate < 1% per year) while taking study treatment and for 6 months after stopping study treatment. Highly effective contraception methods include:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, bilateral tubal occlusion, or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only
when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
• Male sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient
• Placement of an intrauterine device (IUD) or intrauterine system (IUS).
The use of oral (estrogen and progesterone), injected, implanted, or other forms of hormonal contraception (for example hormone vaginal ring or transdermal hormone contraception) cannot be considered as highly effective contraception methods in this study for women of child-bearing potential.
Women are considered post-menopausal and not of child bearing potential if they have had over 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate [generally age from 40 to 59 years], history of vasomotor symptoms [e.g. hot flush]) in the absence of other medical justification or have had surgical bilateral oophorectomy (with or without hysterectomy) or total hysterectomy at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 90 days after stopping study treatment. A condom is required for all sexually active male patients to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male patients must not donate sperm for the time period specified above.
If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF.
