IRB Study Number 21-952
Status Recruiting
Phase Phase 2
Institute Taussig Cancer Institute
Description
Primary Objective
• To evaluate the anticancer efficacy of INBRX-109 in the ITT population as measured by PFS per RECISTv1.1, assessed by central IRR, comparing INBRX-109 and placebo.
Secondary Objectives
• To evaluate the anticancer efficacy of INBRX-109 as measured by overall survival (OS) comparing INBRX-109 and placebo. Note: The study is not expected to a show statistically significant difference in the survival curves between the two treatment arms, INBRX-109 and placebo, due to the crossover design. The main goal of the OS analysis is to rule out a detrimental survival effect of INBRX-109 (e.g., due to toxicity).
• To evaluate the anticancer efficacy of INBRX-109 as measured by objective response rate (ORR) per RECISTv1.1, assessed by central IRR, comparing INBRX-109 and placebo.
o To evaluate duration of response (DOR) per RECISTv1.1, assessed by central IRR, comparing INBRX-109 and placebo.
• To evaluate the anticancer efficacy of INBRX-109 as measured by DCR per RECISTv1.1, assessed by central IRR, comparing INBRX-109 and placebo.
• To evaluate the anticancer efficacy of INBRX-109 as measured by PFS per RECISTv1.1, by Investigator assessment, comparing INBRX-109 and placebo.
• To evaluate the quality of life (QoL) (i.e., EORTC QLQ-C30) comparing INBRX-109 and placebo.
• To evaluate the safety and tolerability of INBRX-109.
• To characterize the pharmacokinetics of INBRX-109.
• To evaluate the frequency of ADA, and neutralizing ADA (NAb), against INBRX-109 and to explore the potential relationship with safety, pharmacokinetics and efficacy of INBRX-109.
Inclusion Criteria
- Males or females aged ≥ 18 to ≤ 85 years.
Note: potential inclusion of patients who are chronologically older than 85 years, but with ECOG 0 and a younger biologic age per comprehensive geriatric assessment, must be based on discussion with the Medical Monitor or Study Director.
- Conventional (or primary) chondrosarcoma (Note: must be confirmed by local institutional or reference pathology review, but this confirmation is not required for enrollment)
• Metastatic or unresectable (i.e., not amenable to tumor resection with a curative intent)
• The availability of archival tissue or a fresh cancer biopsy is mandatory for enrollment.
− Note: A confirmation of IDH mutational status (per CLIA-certified assay or equivalent) is required for stratification prior to randomization, any status is allowed, i.e. IDH1, IDH2 or wildtype.
• Any number of prior lines of systemic therapy are allowed.
− Note: Since there are no FDA/EMA approved systemic therapies for this population, patients with unresectable and/or metastatic disease who have not received prior systemic therapy may be eligible, provided that they have exhausted all clinically relevant (localized and/or palliative) treatment options as per investigator’s preference as per local practice guidelines.
Furthermore, patients with oligometastatic disease (low disease burden, resectable) must have exhausted all clinically relevant options including palliative radiation, surgery or chemotherapy with non-curative intent.
- Measurable disease by RECIST v1.1.
• 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.
- Evidence of confirmed radiographic disease progression per RECISTv1.1 criteria within 6 months prior to the start of study treatment.
• Note: Potential inclusion of patients with progression, which was not determined or confirmed by RECISTv1.1 (e.g., bone only disease), must be discussed and approved by the Medical Monitor or Study Director.
- Adequate laboratory parameters:
• Adequate hepatic function:
− AST, ALT and GGT within ULN, and Bilirubin within ULN for patients without liver metastasis
− AST, ALT and GGT ≤ 2.5 x ULN, and Bilirubin ≤ 1.5 x ULN for patients with liver metastasis.
− Exception: Bilirubin ≤ 2.5 x ULN for patients who have known serum bilirubin increases due to underlying Gilbert’s Syndrome or familial benign unconjugated hyperbilirubinemia.
• Adequate renal function: Creatinine clearance ≥ 50 mL/min.
• Adequate hematologic function: ANC ≥ 1500 cells/μL, Platelet count ≥ 100,000/μL and Hemoglobin ≥ 8.0 g/dL.
• Coagulation tests: aPTT ≤ 1.5 x ULN and INR ≤ 1.7 without anti-coagulants.
− Exception: INR 2 to ≤ 3 is acceptable for patients on anticoagulation therapy.
- Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.
• Exception: non-frail, physically active patients with compromised mobility due to prior cancer surgery (e.g. limb amputation, hemipelvectomy etc) should be discussed with the Medical Monitor or Study Director.
Estimated life expectancy, in the documented judgment of the Investigator, of at least 12 weeks.
Recovery from all reversible AEs of previous anticancer therapies to baseline or CTCAEv5.0 Grade 1 or better. Inclusion of patients with other not clinically significant toxicities (e.g., alopecia, Grade ≤ 2 sensory peripheral neuropathy or lymphopenia etc.) should be discussed with the Medical Monitor or Study Director.
Must have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of any study procedures.
• Note: Patients with a personal or financial relationship with the sponsor, a contractual relationship with the investigator or the trial site, or who are in custody or have been sanctioned by an official or court order will not be eligible to participate.
- Male and female patients of childbearing potential must be willing to completely abstain or agree to use a highly effective method of contraception (i.e., less than 1% failure rate), from the time of signing informed consent and for the duration of study participation through 3 months, following the last dose of study treatment. See protocol Appendix 2 for a list of some examples of highly effective contraception.
• 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 (i.e., has had menses at any time in the preceding 12 consecutive months).
• A man of childbearing potential is any man who has not been surgically sterilized (i.e., has not undergone bilateral orchiectomy).
Exclusion Criteria
Any prior 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, whichever is shorter.
• 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.
- Receipt of radiotherapy (with the exception of palliative localized radiation) within 4 weeks 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 the liver (total calculated dose to the liver >10 Gy) are excluded.
- Receipt of liver-directed therapies (eg, radio frequency ablation [RFA], trans-arterial chemoembolization [TACE], cryotherapy, stereotactic body radiation therapy [SBRT], or others) within 12 months prior to the first dose of study treatment.
• Note: Patients who had prior radioembolization with Yttrium-90 beads 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 suggest an increased potential for an adverse hypersensitivity to INBRX-109.
Non-conventional CSs, eg, clear-cell, mesenchymal, extra-skeletal myxoid, myxoid, and dedifferentiated CS.
• Note: Conventional CSs with myxoid features are considered Grade 2 conventional CSs and are allowed in this study.
- 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 and the Sponsor for potential inclusion.
- Symptomatic active CNS metastases or leptomeningeal disease.
• Exception: Patients with asymptomatic CNS metastases are eligible if controlled, defined as ≥4 weeks of stable neurologic function following CNS directed therapy (stereotactic radiotherapy, definitive surgical resection, and/or whole brain radiotherapy); do not require steroids; and there is no evidence of CNS PD 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.
- Chronic liver diseases including but not limited to NAFLD or NASH, alcohol-related liver disease, cirrhosis, hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, liver hemangioma, hepatic or biliary autoimmune disorders (eg, primary biliary cholangitis, AIH), history of portal or hepatic vein thrombosis, sinusoidal occlusion syndrome.
• Note: Liver imaging is required for all patients to rule out chronic liver diseases. When NAFLD, NASH, fibrosis, or cirrhosis are suspected, liver MRI or MRE are preferred, and the percentage of liver fat content should be provided. CT scan without contrast (or precontrast, if the baseline tumor assessment scans are used), ultrasound, or transient elastography are acceptable to rule out other chronic liver diseases. If a CT scan is used, the attenuation value of liver and spleen should be provided in HU.
• Exception: The eligibility of patients with clinically nonsignificant solitary hemangiomas should be discussed with the Medical Monitor.
• 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 HSI ≥36 and 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 by liver imaging. These cases must be reviewed and discussed with the Medical Monitor.
Acute viral (including hepatitis A, D, E viruses, CMV, EBV) or toxic liver disease within 12 months prior to the first dose of study treatment.
Any evidence or history of HBV, HCV, or HIV infection.
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).
Major surgery within 4 weeks prior to this study.
Clinically significant bacterial, fungal, or viral infection requiring anti-infective treatment within 2 weeks prior to this study.
Pregnant or nursing females, female patients of childbearing potential, and fertile male patients with female partners of childbearing potential unwilling use acceptable contraception methods at least 28 days before the first dose of study treatment until 90 days after the last dose of study treatment.
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 are allowed for pain management. Cannabinoids are allowed for patients from states/countries that have legalized their 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 likely in the judgment of the Investigator to interfere with compliance to protocol treatment/research, or which might compromise the safety of the patient or interfere with participation in the study or compromise the study objective.
Note: Patients with the following ongoing comorbid conditions are excluded:
a. Acute deep vein thrombosis or clinically significant pulmonary embolism not resolved or stable for at least 3 months prior to the start of study treatment.
b. Clinically significant, uncontrolled with medication type 2 diabetes mellitus; metabolic syndrome or pre-diabetes; insulin-resistance (with hemoglobin A1c >6%).
c. Clinically significant, uncontrolled with medication hypothyroidism.
d. Clinically significant, uncontrolled with medication hypertension Stage >1.
e. Clinically significant, uncontrolled with medication hypertriglyceridemia.
f. Hypoxia with oxygen saturation <92%.
g. Encephalopathy Stage ≥1.
- Any evidence or history of multiple sclerosis (MS) or other demyelinating disorders.
▪ 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.
