Clinical Trials

IRB Study Number 22-351

Status Recruiting

Phase Phase 1

Institute Taussig Cancer Institute

Description

Primary Objectives

• To assess the safety and tolerability of INBRX-109 administered intravenously (IV) in combination with distinct chemotherapies in adults and/or adolescents with advanced/metastatic malignant pleural mesothelioma, pancreatic adenocarcinoma, Ewing sarcoma, colorectal adenocarcinoma, and succinate dehydrogenase (SDH)-deficient solid tumors or gastrointestinal stromal tumor (GIST).

• To assess the antitumor efficacy of INBRX-109 administered IV in combination with irinotecan and temozolomide in Ewing sarcoma by objective response rate (ORR) and duration of response (DOR).

Secondary Objectives

• To assess the pharmacokinetics (PK) of INBRX-109 as a single agent, and of INBRX-109 in combination with distinct chemotherapies.

• To assess the immunogenicity of INBRX-109 as a single agent, and of INBRX-109 in combination with distinct chemotherapies.

• To assess median progression-free survival (PFS) in Ewing sarcoma.

Reference: noveltc

Inclusion Criteria

1. Males or females aged ≥12 to <85 years of age for Ewing sarcoma and 18 to <85 years of age for other tumors.

Note: for adolescents, body weight must be ≥30 kg.

1. Tumor types and tissue availability:

• Part 1 dose-escalation cohorts: concluded.

• Part 2 single-agent expansion cohorts: closed for further enrollment.

• Part 3 combination therapy expansion Cohort C1: closed for further enrollment.

• Part 3 combination therapy expansion Cohort C2: closed for further enrollment.

• Part 3 combination therapy expansion Cohort C3c: histologically confirmed Ewing sarcoma with a classical fusion.

o Patients with locally advanced or metastatic, unresectable, relapsed, or refractory disease who have received at least 1 but no more than 2 prior lines of systemic treatment with a preferred first line chemotherapy regimens (eg, vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide [VDC/IE]; vincristine, doxorubicin, and ifosfamide [VAI]; vincristine, ifosfamide, doxorubicin, and etoposide [VIDE]; vincristine, doxorubicin, cyclophosphamide [VDC]; or topotecan-based regimens), and who are candidates for irinotecan and TMZ regimen. Prior systemic therapy in adjuvant or neoadjuvant (definitive) setting is allowed.

o Patients with documented disease progression within 6 months of completion of their adjuvant or neoadjuvant therapy are considered primary refractory in the front-line setting.

o Patients need to have documented presence of EWSR1-FLI1 (or other less common EWSR1-ERG, EWSR1-FEV) rearrangement, which must be confirmed by a local institutional pathology laboratory or reference laboratory pathology review.

o Submission of archival tissue is required for enrollment. If tissue from more than 1 prior biopsy (or from multiple tumor sites) is available, these additional samples may be submitted for biomarker analysis. For patients who do not have archival tissue available, a fresh biopsy will be necessary.

• Part 3 combination therapy expansion Cohort C4d: colorectal adenocarcinoma.

o Patients with locally advanced or metastatic, unresectable disease, who have received at least 2 but no more than 3 prior lines of systemic therapy.

▪ Previous treatment with an irinotecan-containing regimen is allowed but not as an immediate prior line of therapy (ie, patients had to receive a non-irinotecan-based treatment regimen before entering the study).

o Submission of archival tissue is required for enrollment. If tissue from more than 1 prior biopsy (or from multiple tumor sites) is available, these additional samples may be submitted for biomarker analysis. For patients who do not have archival tissue available, a fresh biopsy will be necessary.

• Part 3 combination therapy expansion Cohort C5c: SDH-deficient solid tumors or GIST with recurrent or refractory, unresectable, or metastatic disease for which there is no known curative therapy.

o Eligible patients must have documented loss of SDHB expression by IHC (if available) and/or assessment of SDH (A/B/C/D) gene mutation(s) by next generation sequencing, per Clinical Laboratory Improvement Amendments (CLIA)-certified assays (commercially available or institutional).

o Patients with GIST must have pathologically confirmed disease.

o Previously untreated patients are eligible due to the absence of approved standard systemic therapy.

o Patients previously treated with other therapies for GIST (eg, imatinib, sunitinib, regorafenib) will also be eligible.

o Submission of archival tissue is required for enrollment. If tissue from more than 1 prior biopsy (or from multiple tumor sites) is available, these additional samples may be submitted for biomarker analysis. For patients who do not have archival tissue available, a fresh biopsy will be necessary.

1. Measurable disease, as defined by RECIST v1.1 or modified RECIST criteria.

Note: Tumor lesions that are located in a previously irradiated (or other locally treated) area will be considered measurable, provided there has been clear imaging-based progression of the lesions since the time of radiation.

Note: Patients with only limited disease in the bone or bone marrow are only allowed if soft-tissue component is present.

1. Adequate hepatic function, defined by the following:

• Patients without liver metastasis:

a. AST and ALT within the upper limit of normal (ULN) and gamma-glutamyl transferase (GGT) ≤1.5 × ULN and

b. Bilirubin within ULN.

• Patients with liver metastasis:

a. AST, ALT, and GGT ≤2.5 × ULN, and

b. Bilirubin ≤1.5 × ULN.

• Exception: Bilirubin ≤2.5 × ULN is allowed for patients who have known serum bilirubin increases due to underlying Gilbert’s syndrome or familial benign unconjugated hyperbilirubinemia.

o Because Gilbert’s syndrome is associated with a mutation in uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) gene, any patient with Ewing sarcoma with known history of this syndrome must be screened for UGT1A1 gene variant. If needed, the dose of irinotecan should be adjusted. Note: As GGT is sensitive for liver function, it can be evaluated several times during Screening. ULN is based on normal ranges for each participating institution.

1. Adequate renal function:

• Estimated creatinine CL ≥30 mL/min in Part 3 Cohort C3 and ≥50 mL/min in Part 3 Cohort C5 calculated using Schwartz’s formula (for patients ≤18 years) or Cockcroft-Gault formula (for patients >18 years) (Appendix 2).

1. Adequate hematologic function:

• Absolute neutrophil count (ANC) ≥1,500 cells/μL.

• Platelet count ≥100,000/μL.

• Hemoglobin ≥8.0 g/dL.

1. Coagulation tests:

• Activated partial thromboplastin time (aPTT) ≤1.5 × ULN.

• International normalized ratio (INR) ≤1.7 without anticoagulants.

• Exception: INR 2 to ≤3 is acceptable for patients on anticoagulation.

1. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1, or Karnofsky Performance Status score of ≥60, or Lansky Play-Performance Scale for Children score ≥60 (for patients <16 years).

• Exception: inclusion of non-frail, physically active patients with compromised mobility due to prior cancer surgery (eg, limb amputation, hemipelvectomy) should be discussed with the Medical Monitor and/or Study Director. Performance status scales are presented in Appendix 3.

1. Estimated life expectancy, in the documented judgment of the Investigator, of at least 12 weeks.

2. Fertile male patients with female partners of childbearing potential and female patients of childbearing potential must be willing to completely abstain from or agree to use a highly effective method of contraception (ie, less than 1% failure rate). If not abstaining, fertile male patients with female partners of childbearing potential must be willing to use a highly effective method of contraception at least 28 days before the first dose of study treatment until at least 3 months after the last dose of study treatment. If not abstaining, female patients of childbearing potential must be willing to use a highly effective method of contraception at least 28 days before the first dose of study treatment until at least 6 months after the last dose of TMZ or irinotecan or at least 3 months after the last dose of INBRX-109, whichever is later. Examples of highly effective contraception are presented in Appendix 4.

a. A woman of childbearing potential is any woman, regardless of sexual orientation, who meets the following criteria: 1. has not undergone a hysterectomy or bilateral oophorectomy; or 2. has not been naturally postmenopausal for at least 12 consecutive months (ie, has had menses at any time in the preceding 12 consecutive months).

b. A man of childbearing potential is any man who has not been surgically sterilized (ie, has not undergone bilateral orchiectomy).

1. Recovery from all reversible AEs of previous anticancer therapies to Baseline or NCI CTCAE v5.0 Grade 1 or better. Inclusion of patients with other not clinically significant toxicities (eg, alopecia [any Grade] and Grade ≤2 sensory peripheral neuropathy, vitiligo, electrolyte abnormalities, lymphopenia) should be discussed with the Medical Monitor or Study Director.

2. Ability to understand and the willingness to sign a written informed consent/assent document, which must be obtained prior to initiation of any study procedures.

Note: Patients with a personal or financial relationship to the Sponsor, a contractual relationship with the Investigator or the study site, or who are in custody or have been sanctioned by an official or court order will not be eligible to participate.

Exclusion Criteria

1. Any prior treatment with or exposure to DR5 agonists.

2. Receipt of any anticancer therapy (including investigational agents) within 4 weeks or within 5 half-lives prior to the first dose of study treatment.

• Exception: Hormonal and/or hormonal replacement therapy.

• Note: patients who received pazopanib as an immediate prior line must have a 4-week washout and no evidence of prior or residual hepatotoxicity.

• Note: patients with any history or evidence of Grade ≥3 hepatotoxicity on prior anticancer therapy are excluded.

1. Allergy or sensitivity to INBRX-109 or known allergies to Chinese hamster ovary (CHO)-cell produced antibodies, which, in the opinion of the Investigator, suggests an increased potential for an adverse hypersensitivity to INBRX-109.

2. Receipt of radiotherapy (with the exception of palliative localized radiation, ie, 1 week) within 4 weeks prior to the first dose of study treatment, and liver-directed therapies (ie, radio frequency ablation [RFA], trans-arterial chemoembolization [TACE]/embolization, cryotherapy, stereotactic body radiation therapy [SBRT]) within 12 months prior to the first dose of study treatment. Patients must have recovered from all radiation-related toxicities and not require corticosteroids.

• Note: 1-week washout is required for palliative radiation to non-central nervous system (CNS) disease.

• Note: Patients who had prior radiotherapy involving liver (total calculated dose to the liver ≥10 Gy) are excluded.

• Note: Patients who had prior radioembolization with Yttrium-90 beads are excluded.

1. Has undergone allogeneic hematopoietic stem cell or bone marrow transplantation within the last 5 years.

• Exception: Patients who have had a stem cell or bone marrow transplant >5 years ago are eligible for enrollment, as long as there are no symptoms of graft-versus-host disease (GVHD).

1. Prior or concurrent malignancies.

• Exception: Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessments of INBRX-109. These cases must be reviewed and discussed with the Medical Monitor or Study Director for potential inclusion.

1. Hematologic malignancies (ie, acute lymphoblastic leukemia [ALL], acute myeloid leukemia [AML], myelodysplastic syndrome [MDS], CLL, chronic myelogenous leukemia [CML], non-Hodgkin lymphoma [NHL], Hodgkin lymphoma, and multiple myeloma).

2. Symptomatic active primary CNS tumors, leptomeningeal disease, and CNS metastases.

• Exception: Patients with asymptomatic CNS metastases are eligible if there is no evidence of CNS disease progression as determined by radiographic imaging within 4 weeks prior to the first dose of study treatment.

o Note: Patients with spinal cord metastases are allowed.

o Note: Patients with untreated, uncontrolled, ongoing spinal cord compression are excluded.

o Note: Patients with any evidence or history of multiple sclerosis (MS) or other demyelinating disorders are excluded.

o Note: For patients without known or suspected CNS metastases, or any other neurologic findings, brain imaging is not required at Baseline to rule out MS or potential demyelinating disorders.

1. Any chronic liver disease including but not limited to cirrhosis, nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH), alcohol-related liver disease, hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, multiple liver hemangioma (except incidental finding of clinically nonsignificant liver hemangioma), hepatic or biliary autoimmune disorders (ie, primary biliary cholangitis, autoimmune hepatitis), history of portal or hepatic vein thrombosis, and sinusoidal occlusion syndrome.

• Note: Patients with any imaging evidence of NAFLD, NASH, fibrosis, or cirrhosis, regardless of prior history and liver function tests (LFTs) at Baseline are excluded from the study. Liver magnetic resonance imaging (MRI) or magnetic resonance elastography (MRE) are preferred. Other imaging modalities, such as computed tomography (CT; without contrast), ultrasound, and transient elastography, are acceptable to rule out other chronic liver diseases.

• Exception: Patients aged <45 years with NAFLD detected by imaging may participate in the study if adequate hepatic function as defined in the inclusion criteria is confirmed. Unclear cases must be reviewed and discussed with the Medical Monitor or Study Director for potential inclusion.

• Note: Patients aged >45 years with NAFLD are excluded from the study.

• Patients aged >65 years and with BMI >30 kg/m2 are excluded from the study. Patients aged ≥45 years with hepatic steatosis index (HSI) ≥36 and fatty liver index (FLI) ≥60 are also excluded from the study. If one of the values (HSI or FLI) is in the acceptable range and the other is above the cutoff, the patient may still be eligible for the study if fatty liver is excluded at imaging. These cases must be reviewed and discussed with the Medical Monitor.

1. Acute viral liver disease (including hepatitis A, D, or E viruses [HAV, HDV, or HEV], cytomegalovirus [CMV], and Epstein-Barr virus [EBV]) or toxic liver disease within 12 months prior to the first dose of study treatment.

2. Any evidence or history of hepatitis B virus (HBV), hepatitis C virus (HCV), or HIV infection.

• Note: If test results for HBV and HCV infection are ≥1 month old or not available in medical history, they must be confirmed by Baseline test result obtained during Screening. Test results for HIV do not need to be repeated.

1. For Part 3:

• Cohort C3, with treatment with irinotecan and TMZ:

a. Known sensitivity to irinotecan or TMZ.

b. Any contraindications to TMZ or irinotecan.

• Cohort C4, with treatment with FOLFIRI:

a. Known sensitivity to FU, leucovorin, or irinotecan.

b. Any contraindications to FU, leucovorin, or irinotecan.

• Cohort C5, with treatment with TMZ:

a. Any history of prior Grade ≥3 toxicity to TMZ.

b. Known sensitivity to TMZ.

c. Any contraindications to TMZ.

1. Clinically significant cardiac condition, including myocardial infarction, uncontrolled angina, cerebrovascular accident, or other acute uncontrolled heart disease <3 months prior to enrollment; left ventricular ejection fraction (LVEF) <50% or shortening fraction <28% (echocardiogram is not required at Screening); New York Heart Association (NYHA) Class III or IV congestive heart failure; or uncontrolled hypertension Stage >1.

Note: The NYHA classification does not apply to adolescent patients. Cardiac condition of adolescent patients should be assessed per institutional and/or national guidelines.

1. Acute, hemodynamically significant deep vein thrombosis or clinically significant pulmonary embolism not resolved or stable for at least 3 months prior to the start of study treatment.

2. Major surgery within 4 weeks prior to enrollment in this study.

3. Systemic clinically significant bacterial, fungal, or viral infection requiring anti-infective treatment within 2 weeks prior to the first dose of study treatment.

4. Pregnant or nursing females.

5. Any known, documented, or suspected history of illicit substance abuse that would preclude patient from participation, unless clinically justified (ie, will not interfere with study participation and/or will not compromise study objectives) per judgment of the Investigator and with approval of the Medical Monitor or Study Director.

• Exception: Physician-prescribed medicinal opioids or cannabinoids without hepatotoxic potential are allowed for pain management. Cannabinoids are allowed for patients from states/countries that have legalized its use.

• Note: Patients with ongoing or prior history of alcoholism are excluded unless they qualify per LFTs and liver imaging.

1. Any other disease or clinically significant abnormality in laboratory parameters, including serious medical or psychiatric illness/condition, which, in the judgment of the Investigator, likely might compromise the safety of the patient or integrity of the study, interfere with the patient participation in the study, or compromise the study objectives.

Note: patients with the following ongoing comorbid conditions are excluded:

a. Clinically significant, uncontrolled with medication type 2 diabetes mellitus; metabolic syndrome or pre-diabetes; or insulin resistance (with hemoglobin A1c >6%).

b. Clinically significant, uncontrolled with medication hypothyroidism.

c. Clinically significant, uncontrolled with medication hypertriglyceridemia and/or hyperlipidemia.

d. Hypoxia with oxygen saturation <92%.

e. Encephalopathy Stage ≥1.

f. Recent or ongoing gastrointestinal disorder that may interfere with absorption of PO administered drugs (eg, gastrectomy).

1. Patients who are receiving strong cytochrome P450 (CYP) 3A inhibitors and/or inducers, and/or UGT1A1 inhibitors within 14 days of Cycle 1 Day 1.