IRB Study Number 24-325
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
Parts 1 and 2: determine the MTD/RP2D of IAM1363 as monotherapy and in combination
Part 3: To characterize the efficacy of IAM1363 as monotherapy and in combination
Secondary Objectives
Parts 1 and 2: To characterize the efficacy of IAM1363 as monotherapy and in combination
Part 3: To further characterize the efficacy of IAM1363 as monotherapy and in combination
Part 3: To evaluate the safety and tolerability of IAM1363 as monotherapy and in combination
All Parts: To evaluate the PK of IAM1363
Inclusion Criteria
Age ≥ 18 years
Have relapsed/refractory to standard therapy, or no standard therapy exists that is likely to provide clinical benefit in the opinion of the Investigator
Have progression of disease after the last systemic therapy, or be intolerant of last systemic therapy
Have radiographically measurable disease by either or both of the following:
a. CNS disease: Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM)
b. Non-CNS disease: Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), with sites of disease that have not been previously irradiated or, if the participant has had previous radiation to the target lesion(s), there must be evidence of progression since the radiation
Eastern Cooperative Oncology Group (ECOG) performance score 0-1
Have adequate baseline hematologic parameters as defined by:
a. Hemoglobin ≥8 g/dL unsupported or without transfusion within 7 days prior to C1D1
b. Absolute neutrophil count (ANC) ≥1500 cells/μL, unsupported without granulocyte-colony stimulating factor (G-CSF) within 7 days prior to C1D1
c. Platelets ≥100,000/μL unsupported or without transfusion within 7 days prior to C1D1
Adequate renal function, defined as calculated creatinine clearance ≥60 mL/min per institutional standard
Have adequate liver function as defined by:
a. Total bilirubin ≤1.5 × upper limit of normal (ULN), (≤3.0 × ULN if the participant has documented Gilbert syndrome)
b. Aspartate and alanine aminotransferase (AST and ALT) ≤3.0 × ULN (≤5.0 × ULN with liver involvement)
Have left ventricular ejection fraction (LVEF) ≥50%
Resolved acute effects of any prior therapy to baseline severity or CTCAE v5.0 Grade ≤1 except for AEs not constituting a safety risk per the Investigator. Participants receiving endocrine replacement therapy as a result of an endocrinopathy from a checkpoint inhibitor are not excluded.
Willing to complete all scheduled visits and assessments at the institution administering therapy.
Able to swallow oral medication.
Females of childbearing potential must have a negative serum pregnancy test within 7 days before initiation of study drug dosing (i.e., Cycle 1 Day 1) and, if having sexual intercourse with male partner(s), must agree to use a highly effective method of birth control per Clinical Trial Coordination Group [CTCG] guidance (2024) and 1 additional barrier method and agree to abstain from breastfeeding and donating eggs or retrieving ova for their own use during treatment (i.e., from the time of the negative pregnancy test) and for at least 90 days after receiving their last dose of study drug. Fertile males with female sexual partners must agree to use a highly effective method of birth control per CTCG guidance (2024) and 1 additional barrier method and must not freeze or donate sperm during treatment and for at least 90 days after receiving their last dose of study drug.
Brain metastases at time of enrollment:
a. Allowed in all parts/cohorts
b. Required for all participants with HER2-positive cancers in Part 2, with the exception of participants with HER2-positive NSCLC where presence of brain metastases is not required
c. Must not require immediate local therapy per Investigator’s judgment
d. Should be classified as measurable or non-measurable per RANO-BM criteria (see Section 13.4.2)
- Participants in Part 1 must have a solid tumor with HER2 alterations (e.g., HER2 gene mutations or fusions, HER2 gene amplification, HER2 protein overexpression); HER2 alteration should be established based on a recent archival tissue sample, fresh biopsy, or blood sample (circulating tumor deoxyribonucleic acid [ctDNA]) and confirmed via one of the tests detailed in Table 14.
a. Biopsies should be obtained consistent with American Society of Clinical Oncology (ASCO) guidance as described in the Ethical Framework for Including Research Biopsies in Oncology Clinical Trials: ASCO Research Statement (Levit 2019).
b. In exceptional cases where biopsy is not feasible, but HER2 status has been assessed through liquid biopsy, contact the Medical Monitor to discuss eligibility.
- For participants with HER2-positive breast cancer enrolled in Part 2 and 3 only:
a. Histologically confirmed breast carcinoma
b. HER2 positivity based on testing from an archival tumor tissue sample analyzed by Clinical Laboratory Improvement Act (CLIA)-certified or International Organization for Standardization (ISO)-accredited laboratory, defined as IHC3+, or IHC2+ and HER2 gene amplified by in situ hybridization (ISH) using ASCO-CAP criteria for HER2 testing in breast cancer (Part 2 and Part 3 Cohort C)
c. Prior treatment as follows:
i. Standard therapeutic regimens in the neo/adjuvant and/or metastatic setting.
ii. Part 2:
Must have no standard treatment options with proven clinical benefit available or are otherwise not a candidate for standard treatment options based on the judgment of the treating physician.
Specifically, participants should have received the following HER2-directed agents in any setting: trastuzumab, pertuzumab, T-DXd and either T-DM1 or tucatinib; neratinib is allowed only if given in the neo/adjuvant setting
Participants cannot have received lapatinib, neratinib, pyrotinib, or other experimental TKI in the metastatic setting
iii. Part 3:
- Cohort C prior treatment with trastuzumab, pertuzumab, T-DXd and at least 1 prior HER2 TKI in the metastatic setting is required; no limit to number of prior TKIs
iv. Participants in any part of the study who did not receive prior treatment with required agents because of lack of access (eg, due to reimbursement/insurance coverage or because they were treated prior to regulatory/Health Technology Assessment [HTA] agency approval) are eligible.
- For participants with HER2-positive gastroesophageal cancer (including gastric and GEJ) enrolled in Part 2 and 3 only:
a. Histologically confirmed gastric, GEJ, gastroesophageal adenocarcinoma (GEA)
b. HER2 positivity based on testing from an archival tumor tissue sample analyzed by CLIA-certified or ISO-accredited laboratory, defined as IHC3+, or IHC2+ and HER2 gene amplified by ISH using ASCO-CAP criteria for HER2 testing in GEA
c. Prior treatment as follows:
i. Must have no standard treatment options with proven clinical benefit available or are otherwise not a candidate for standard treatment options based on the judgment of the treating physician
ii. Standard therapeutic regimens in the metastatic setting. Specifically, participants should have received the following HER2-directed agents in the metastatic setting: trastuzumab and T-DXd.
iii. For participants in Part 2 and Part 3 Cohort B, no prior treatment with HER2 TKI is allowed
iv. For Part 3 Cohort C prior treatment with at least 1 HER2 TKI is required
v. Participants in any part of the study who did not receive prior treatment with required agents because of lack of access (eg, due to reimbursement/insurance coverage or because they were treated prior to regulatory/HTA agency approval) are eligible.
- For participants with HER2-positive cancers, other than breast cancer or GEA, enrolled in Part 2 and 3 only:
a. HER2 positivity based on testing from an archival tumor tissue sample analyzed by CLIA-certified or ISO-accredited laboratory, defined as any of the following:
i. IHC 3+
ii. IHC2+ and HER2 amplification by ISH (HER2/CEP17 ratio ≥2.0)
iii. HER2 amplification (by next generation sequencing [NGS])
b. Prior treatment as follows:
i. Standard therapeutic regimens in the metastatic setting. Specifically, standard regimens may include: trastuzumab and T-DXd (ENHERTU®)
ii. Participants must have no standard treatment options with proven clinical benefit available, or will otherwise be prevented/contraindicated from receiving any standard treatment options based on the judgment of the treating physician.
iii. For participants in Part 2 and Part 3 Cohort B, no prior treatment with HER2 TKI is allowed
iv. For Part 3 Cohort C prior treatment with at least 1 HER2 TKI is required.
v. Participants in any part of the study who did not receive prior treatment with required agents because of lack of access (eg, due to reimbursement/insurance coverage or because they were treated prior to regulatory/HTA agency approval) are eligible.
- For participants with HER2 TKD mutant NSCLC enrolled in Part 2 and 3 only:
a. Pathologically documented unresectable and/or metastatic non-squamous NSCLC
b. HER2 TKD mutation (by NGS, polymerase chain reaction [PCR], or Sanger sequencing) from an archival tumor tissue sample analyzed by CLIA-certified or ISO-accredited laboratory. Mutations include:
i. HER2/ERBB2 TKD domain covering amino acid sequence from codons 720-993
ii. HER2 gene fusions
c. Participants in Part 2 and Part 3 Cohorts A and C must have received and failed ≥1 prior therapy in the metastatic setting, which included a platinum-based chemotherapy; previous treatment with T-DXd is allowed.
d. Participants in Part 2 and Part 3 Cohort A must not have received prior treatment with a HER2 TKI.
e. Participants in Part 3 Cohort C are required to have received prior treatment with at least 1 HER2 TKI; no limit to number of prior TKIs.
- For participants with HER2 TKD mutant cancers, other than NSCLC, enrolled in Part 2 and 3 only:
a. HER2 TKD mutation (by NGS, PCR, or Sanger sequencing) from an archival tumor tissue sample analyzed by CLIA-certified or ISO-accredited laboratory. Mutations include:
i. HER2/ERBB2 TKD domain covering amino acid sequence from codons 720-993
ii. HER2 gene fusions
b. Participants in Part 2 and Part 3 Cohorts A and C must have received and progressed on at least 1 prior standard therapy in the metastatic setting; previous treatment with T-DXd is allowed.
c. Participants in Part 2 and Part 3 Cohort A must not have received prior treatment with a HER2 TKI.
d. Participants in Part 3 Cohort C are required to have received prior treatment with at least 1 HER2 TKI.
Exclusion Criteria
Major surgery or significant traumatic injury within 28 days prior to C1D1
Chemotherapy within 21 days prior to C1D1
Use of nitrosoureas or mitomycin C within 6 weeks prior to C1D1
Radiation therapy within 14 days prior to C1D1
Investigational drug use, targeted therapy, or biologic therapy within 28 days or 5 half-lives, whichever is shorter, prior to C1D1
Ongoing systemic infection requiring treatment with antibiotic, antiviral, or antifungal treatment
Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen.
Known or suspected allergy to the investigational agent or any agent given in association with this study
Use of biotin (i.e., vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 μg (NIH-ODS 2022). (Note: Participants who switch from a high dose to a dose of 30 μg/day or less are eligible for study entry.) Use of herbal, alternative, vitamin and food supplements (i.e., PC-spes, saw palmetto, St. John’s wort, etc.) and probiotics must be discontinued before treatment start. Daily multivitamin (provided it does not contain biotin >30 μg/day), calcium, and vitamin D are permitted.
Concomitant use of strong inducers or inhibitors of CYP3A4 or P-gp inhibitors or sensitive substrates of CYP2C9
a. For CYP3A4, consult the FDA Drug Development and Drug Interactions Table of Substrates, Inhibitors and Inducers (FDA, 2023) and the European Medicines Agency (EMA) Guideline on The Investigation of Drug Interactions, 2012. Examples of strong clinical CYP3A4/5 inhibitors include, but are not limited to, cobicistat, danoprevir and ritonavir, elvitegravir and ritonavir, grapefruit juice, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, paritaprevir and ritonavir and ombitasvir (and/or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, tipranavir and ritonavir, telithromycin, troleandomycin, voriconazole, ceritinib, clarithromycin, idelalisib, nefazodone, and nelfinavir.
b. For P-gp substrates, consult the Flockhart Table of drug interactions (Indiana University School of Medicine, 2023), the University of Washington Drug Interaction Database (Certara, 2023), and the EMA Guideline on The Investigation of Drug Interactions, 2012. Examples of clinically significant P-gp substrates include, but are not limited to, dabigatran etexilate, digoxin, fexofenadine (terfenadine carboxylate), colchicine, digitoxin, loperamide, N-methylquinidine, quinidine, talinolol, and vinblastine.
c. Sensitive substrates of CYP2C9 include, but are not limited to, abrocitinib, celecoxib, diclofenac, lesinurad, mefenamic acid, meloxicam, methadone, nateglinide, ospemifene, phenytoin - has narrow therapeutic range, and warfarin - has narrow therapeutic range.
- Clinically significant cardiac disease, defined as any of the following:
a. Clinically significant cardiac arrhythmias including bradyarrhythmias and/or participants who require anti-arrhythmic therapy (excluding beta blockers or digoxin). Participants with controlled atrial fibrillation are not excluded
b. Congenital long QT syndrome or participants taking concomitant medications known to prolong the QT interval (drugs with a low risk of corrected QT interval [QTc] prolongation that are needed for infection control or nausea may be permitted with approval from the Medical Monitor)
c. QT interval corrected using Fridericia formula (QTcF) ≥470 msec at Screening (based on the average of triplicate electrocardiograms [ECGs] at baseline). If the QTc is prolonged in a participant with a pacemaker or bundle branch block, the participant may be enrolled in the study if confirmed by the Medical Monitor.
d. History of clinically significant cardiac disease or congestive heart failure greater than New York Heart Association Class II. Participants must not have unstable angina (anginal symptoms at rest) or new-onset angina with the last 3 months or myocardial infarction within the past 6 months.
e. Uncontrolled hypertension, defined as systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg (or above the 95th age-specific percentile) which has been confirmed by 2 successive measurements despite optimal medical management
f. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), within 3 months before C1D1
Infection with human immunodeficiency virus (HIV)-1 or HIV-2. Exception: Participants with well-controlled HIV (e.g., CD4 >350/mm3 and undetectable viral load) are eligible
Current active liver disease, including hepatitis A (hepatitis A virus immunoglobulin M positive), hepatitis B (hepatitis B virus [HBV] surface antigen positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid [RNA]). Participants with HCV with undetectable virus after treatment are eligible. Participants with a prior history of HBV are eligible if quantitative PCR for HBV DNA is negative. Note that elevated levels of biotin may interfere with viral serology testing.
Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant small bowel resection that would preclude adequate absorption
Presence of a medical or psychiatric condition that, in the opinion of the Principal Investigator in consultation with the Medical Monitor, makes the participant inappropriate for inclusion in this study
Uncontrolled diabetes
Treatment with a long-acting hematopoietic growth factor within 14 days before C1D1 or a short-acting hematopoietic growth factor within 7 days before C1D1
Treatment with high-dose chemotherapy and stem-cell rescue (autologous stem cell transplant) or allogeneic stem cell transplant within 90 days before C1D1. Anti-graft versus host disease (GvHD) agents post-transplant: Participants who are receiving cyclosporine, tacrolimus, or other agents to prevent GvHD post bone marrow transplant are not eligible for this study.
Corticosteroid therapy <0.5 mg/kg/day averaged during the 30 days before C1D1 is permissible but must be discontinued 14 days before C1D1. (Exceptions: [1] participants with documented brain lesions may receive corticosteroids for management of cerebral edema but must be on a stable dose for 14 days before C1D1; [2] inhaled, intranasal, intraocular, topical and intra-articular joint injections are allowed on study)
Coronavirus disease 2019 (COVID-19) vaccinations for 14 days before C1D1
History of solid organ transplantation
History of Grade ≥2 CNS hemorrhage, or any CNS hemorrhage within 28 days before C1D1
Participants requiring immediate local therapy for brain metastases
Prior history of non-infectious interstitial lung disease (ILD). (Exceptions: participants with prior grade 1 ILD that has completely resolved are eligible)
For participants with breast cancer enrolled in Part 2 and 3 only:
a. History of exposure to the following cumulative doses of anthracyclines:
i. Doxorubicin > 360 mg/m2
ii. Epirubicin > 720 mg/m2
iii. Mitoxantrone > 120 mg/m2
iv. Idarubicin > 90 mg/m2
v. Liposomal doxorubicin (e.g., Doxil, Caelyx, Myocet) >550 mg/m2
