Phase 1 Study of INBRX-109 with Irinotecan and Temozolomide in Advanced Solid Tumors, Including Sarcomas, Ewing Sarcoma, and Colorectal Adenocarcinoma
- Trial ID
- 2023-508139-29-00
- Protocol
- Ph1 INBRX-109 Part 3
- Sponsor
- Inhibrx Biosciences Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and tolerability of INBRX-109 when administered intravenously in combination with distinct chemotherapies in adults and/or adolescents with advanced or metastatic Ewing sarcoma, colorectal adenocarcinoma, and succinate dehydrogenase (SDH)-deficient solid tumors or gastrointestinal stromal tumor (GIST). This is clinically relevant as it aims to determine the potential adverse effects and overall safety profile of the treatment regimen, which is crucial for patient management and therapeutic decision-making.
Secondary objectives include:
- To assess the pharmacokinetics (PK) of INBRX-109 in combination with distinct chemotherapies.
- To evaluate the immunogenicity of INBRX-109 in combination with distinct chemotherapies.
- To assess median progression-free survival (PFS) in colorectal adenocarcinoma and Ewing sarcoma.
Participants
The clinical trial involves a total of **95 participants** diagnosed with **advanced or metastatic solid tumors**, specifically targeting Ewing sarcoma, colorectal adenocarcinoma, and succinate dehydrogenase (SDH)-deficient solid tumors or gastrointestinal stromal tumor (GIST). The study population includes both **male and female subjects** aged 12 to less than 85 years for Ewing sarcoma, and 18 to less than 85 years for other tumors, with a requirement for adolescent participants to have a body weight of at least 30 kg. Participants were selected based on their diagnosis and previous treatment history, with specific criteria for tumor types and tissue availability. The trial includes individuals with an estimated life expectancy of at least 12 weeks and requires recovery from previous anticancer therapies to a baseline or better condition. Participants must have adequate hepatic, renal, and hematologic function, and a performance status score indicating they are non-frail and physically active. The trial population is considered vulnerable, and all participants must provide informed consent. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed as an open-label, multicenter, first-in-human, Phase 1 dose escalation and multicohort expansion study. The primary objective is to assess the safety and tolerability of **INBRX-109** administered intravenously in combination with distinct chemotherapies in adults and/or adolescents with advanced or metastatic solid tumors, including Ewing sarcoma, colorectal adenocarcinoma, and succinate dehydrogenase-deficient solid tumors or gastrointestinal stromal tumor. The trial will also evaluate the antitumor efficacy of INBRX-109 in combination with **irinotecan** and **temozolomide** in Ewing sarcoma, and with fluorouracil, leucovorin, and irinotecan in colorectal adenocarcinoma, by overall response rate and duration of response. The trial is expected to commence recruitment on April 1, 2024, and conclude by August 31, 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, tumor type, and adequate organ function. The inclusion criteria specify that participants must be aged 12 to 84 years for Ewing sarcoma and 18 to 84 years for other tumors, with an estimated life expectancy of at least 12 weeks. Following the screening, participants will attend regular follow-up visits to monitor safety, tolerability, and efficacy outcomes. These visits will include assessments of treatment-emergent adverse events, clinical response, and pharmacokinetic parameters. The end-of-study visit will occur after the final treatment cycle to evaluate long-term outcomes and any residual adverse effects.
The expected length of participant involvement in the trial is contingent upon the treatment regimen and response, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. Conditions that may lead to early termination include the occurrence of dose-limiting toxicities or severe adverse events as defined by the National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0. The trial's design ensures rigorous monitoring to safeguard participant safety while aiming to achieve the study's primary and secondary endpoints.
Treatment
The clinical trial involves the administration of several experimental medications, including **irinotecan hydrochloride trihydrate**, marketed as Campto 20 mg/ml. This medication is provided as a **solution for infusion** and is administered via **intravenous infusion**. The frequency and dosage are determined based on the specific protocol requirements for the trial. Irinotecan hydrochloride trihydrate is a chemical entity produced by Pfizer S.A. and is utilized in combination with other chemotherapeutic agents to assess its efficacy in treating various solid tumors.
Another experimental medication used in the trial is **temozolomide**, available in multiple dosages as hard capsules, including 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg. Temozolomide is administered **orally** and is a chemical entity produced by Merck Sharp & Dohme BV. The dosing schedule is tailored to the trial's protocol, and participant compliance is monitored to ensure adherence to the treatment regimen.
The trial also includes the use of **ozekibart**, a protein-based experimental medication provided as a **powder for solution for injection**. Ozekibart is administered via **intravenous** route and is produced by Inhibrx Biosciences Inc. This medication is evaluated for its safety and efficacy in combination with other chemotherapeutic agents in the treatment of advanced or metastatic solid tumors.
In addition to the experimental medications, the trial may involve the use of standard-of-care therapies or comparator treatments as per the study design. Participant compliance with the dosing schedules is closely monitored to ensure the integrity of the trial data. The administration of these medications is conducted under strict clinical supervision to assess their safety, tolerability, and antitumor efficacy in the specified patient populations.
Efficacy
The efficacy of the clinical trial will be assessed through several key parameters. The primary endpoints include the overall response rate (ORR) and duration of response (DOR) in patients with colorectal adenocarcinoma and Ewing sarcoma, evaluated according to RECIST version 1.1 criteria. These endpoints will provide insights into the antitumor efficacy of INBRX-109 when administered intravenously in combination with irinotecan and temozolomide for Ewing sarcoma, and with fluorouracil, leucovorin, and irinotecan (FOLFIRI) for colorectal adenocarcinoma.
Secondary endpoints will include pharmacokinetic (PK) parameters such as AUC0-inf, AUC0-last, AUC0-21d or AUC0-28d, Cmax, Ctrough, and Tmax, which will be estimated using standard non-compartmental analysis. Additional PK parameters, including λz, t½, Vd, CL, and accumulation ratios (RCmax, RCtrough), will be calculated if data permit. The incidence, quantity, and effect of anti-drug antibodies (ADAs) against INBRX-109 will also be evaluated. Furthermore, median progression-free survival (PFS) will be assessed for both colorectal adenocarcinoma and Ewing sarcoma.
The collection and analysis of these efficacy parameters will be conducted at specified intervals throughout the trial, ensuring a comprehensive evaluation of the treatment's impact on the targeted conditions. The use of validated scales and criteria, such as RECIST v1.1, will ensure the reliability and accuracy of the efficacy assessments.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Males or females aged ≥12 to <85 years of age for Ewing sarcoma and 18 to <85 years of age for other tumors. Note: body weight for adolescent patients must be ≥30 kg. Note: Study sites in the Netherlands are only allowed to enroll patients ≥16 years of age.
- Tumor types and tissue availability: 2a. Histologically confirmed Ewing sarcoma with a classical fusion. - Patients with locally advanced or metastatic, unnresectable, relapsed, or refractory disease who have received at least 1 but no more than 2 prior lines of systemic treatment and who are candidates for irinotecan and TMZ regimens. Prior systemic therapy in adjuvant or neoadjuvant (definitive) setting is allowed. - 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. - Patients need to have documented presence of EWSR1-FLI1 (or EWSR1-ERG, EWSR1-FEV) rearrangement, which must be confirmed by a local institutional pathology laboratory or reference laboratory pathology review. - Submission of archival tissue is required for enrollment. For patients who do not have archival tissue available, a fresh biopsy will be necessary.
- 2b: 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. o 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. For patients who do not have archival tissue available, a fresh biopsy will be necessary
- Measurable disease, as defined by RECIST version 1.1 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.
- Adequate hepatic function, defined by the following: • Patients without liver metastasis: a. AST and ALT within the upper limit of normal (ULN), 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.
- Adequate renal function: •Estimated creatinine CL ≥30 mL/min in Part 3 Cohort C3 and ≥50 mL/min in Part 3 Cohort C4 calculated using Schwartz’s formula (for patients ≤18 years) or Cockcroft Gault formula (for patients >18 years)
- Adequate hematologic function: - Absolute neutrophil count (ANC) ≥1,500 cells/μL. - Platelet count ≥100,000/μL. - Hemoglobin ≥8.0 g/dL.
- 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.
- 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.
- Estimated life expectancy, in the documented judgment of the Investigator, of at least 12 weeks.
- Fertile male patients with female partners of childbearing potential and female patients of childbearing potential must agree to avoid impregnating a partner or becoming pregnant, respectively. Fertile male patients with female partners of childbearing potential must be willing to use acceptable methods 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. Female patients of childbearing potential must be willing to use acceptable methods 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. Male patients must refrain from donating sperm during this period. a. A woman is considered of childbearing potential following menarche and until becoming post menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Postmenopausal state is defined as no menses for 12 months without an alternative medical cause. b. A man is considered fertile after puberty unless permanently sterile by bilateral orchiectomy.
- 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.
- 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.
Exclusion Criteria
- Any prior treatment with or exposure to DR5 agonists.
- 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.
- 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.
- 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 within 12 months prior to the first dose of study treatment. Patients must have recovered from all radiation-related toxicities and not require corticosteroids. o Note: 1-week washout is required for palliative radiation to non-central nervous system (CNS) disease. o Note: Patients who had prior radioembolization with Yttrium-90 beads are excluded. o Note: Patients who had prior radiotherapy involving liver (total calculated dose to the liver ≥10 Gy) are excluded.
- 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).
- 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.
- 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).
- 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. - Note: Patients with spinal cord metastases are allowed. - Note: Patients with untreated, uncontrolled, ongoing spinal cord compression are excluded. - Note: Patients with any evidence or history of multiple sclerosis (MS) or other demyelinating disorders are excluded.
- 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. o 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, transient elastography, are acceptable to rule out other chronic liver diseases. o 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. o Note: Patients aged >45 years with NAFLD are excluded from the study. o 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.
- Acute viral liver desease (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.
- 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 the medical history, they must be confirmed by Baseline test result obtained during Screening. Test results for HIV do not need to be repeated.
- 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.
- 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.
- 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.
- Major surgery within 4 weeks prior to enrollment in this study.
- Systemic clinically significant bacterial, fungal, or viral infection requiring anti-infective treatment within 2 weeks prior to the first dose of study treatment.
- Pregnant or nursing females; and female patients of childbearing potential and fertile male patients with female partners of childbearing potential unwilling use acceptable contraception methods as presented in inclusion criterion #10.
- 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.
- 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; insulin-resistance (with 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 orally administered drugs (eg, gastrectomy).
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 01 Apr 2024 | 10 |
 Italy | Recruiting | 01 Apr 2024 | 7 |
 The Netherlands | Recruiting | 01 Apr 2024 | — |
 Spain | Recruiting | 01 Apr 2024 | 10 |
| Netherlands | — | — | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Campto 20 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Test | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENIOUS INFUSION | — | — | PRD1759275 |
Campto 20 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Test | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENIOUS INFUSION | — | — | PRD1759435 |
DEXAMETHASONE | Other | PHF00043MIG | ORAL AND IV | — | — | SCP25844939 |
Temodal 180 mg hard capsules | Test | HARD CAPSULES | ORAL | — | — | PRD2864124 |
Temodal 5 mg hard capsules | Test | HARD CAPSULES | ORAL | — | — | PRD2864118 |
Temodal 140 mg hard capsules | Test | HARD CAPSULES | ORAL | — | — | PRD2864131 |
Temodal 100 mg hard capsules | Test | HARD CAPSULES | ORAL | — | — | PRD2864123 |
Campto 20 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Test | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS INFUSION | — | — | PRD1759125 |
Temodal 20 mg hard capsules | Test | HARD CAPSULES | ORAL | — | — | PRD2864122 |
Temodal 250 mg hard capsules | Test | HARD CAPSULES | ORAL | — | — | PRD2864128 |