A Randomized, Blinded, Placebo-controlled, Phase 2 Study of INBRX-109 in Unresectable or Metastatic Conventional Chondrosarcoma

To be eligible for study entry patients must satisfy all of the following
criteria:
1. Males or females aged >= 18 to <= 85 years.
Note: Potential inclusion of patients who are chronologically older than 85
years, but with Eastern Cooperative Group Performance Status (ECOG PS) 0 and a
younger biologic age per comprehensive geriatric assessment, must be based on
discussion with the Medical Monitor or Study Director.
2. 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
curative intent),
• The availability of archival tissue or a fresh cancer biopsy is mandatory for
enrollment.
- Note: A confirmation of IDH mutational status (per Clinical Laboratory
Improvement Amendments [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.
3. Measurable disease by RECISTv1.1.
• 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.
4. Evidence of confirmed radiographic disease progression per RECISTv1.1
criteria within 6 months prior to the start of the 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.
5. 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.
- Note: As transient elevations in GGT can occur due to nonhepatobiliary
etiologies, the test can be repeated during Screening after consultation with
the
Medical Monitor.
• Adequate renal function: Creatinine clearance >= 50 mL/min.
• Adequate hematologic function: Absolute neutrophil count (ANC) >= 1500
cells/µL, Platelet count >= 100,000/µL and Hemoglobin >= 8.0 g/dL.
• Coagulation tests: Activated partial thromboplastin time (aPTT) <= 1.5 x ULN
and international normalized ratio (INR) <= 1.7 without anti-coagulants.
* Protocol only requires to test for standard coagulation tests. Exception: INR
2 to <= 3 is acceptable for patients on anticoagulation therapy. If a subject is
using a DOAC, it will be requested that they adhere to their therapy with
standard of care monitoring as needed per local practice.
6. ECOG PS of 0 or 1.
• Exception: Inclusion of non-frail, physically active patients with
compromised mobility due to prior cancer surgery (e.g. limb amputation,
hemipelvectomy) should be discussed with the Medical Monitor or Study
Director.
7. Estimated life expectancy, in the documented judgment of the Investigator,
of at least 12 weeks.
8. Recovery from all reversible AEs of previous anticancer therapies to
baseline or NCI 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) should be discussed with the Medical
Monitor or Study Director.
9. Must have the ability to understand and sign a written informed consent form
(ICF), 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 study site, or who are in
custody or have been sanctioned by an official or court order will not be
eligible to participate.
10. 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. They must be willing to use
acceptable methods of contraception at least 28 days before the first dose of
study treatment until 90 days after the last dose of study treatment.
• A woman is considered of childbearing potential following menarche and until
becoming postmenopausal 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.
• A man is considered fertile after puberty unless permanently sterile by
bilateral orchiectomy.

Patients will be excluded from the study if one or more of the following
criteria is/are applicable:
1. Any prior exposure to DR5 agonists.
2. Receipt of any anti-cancer 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 anti cancer therapy are excluded.
3. Receipt of radiotherapy (with the exception of palliative localized
radiation) within 4 weeks to the first dose of study treatment. Patients must
have recovered from all radiation-related toxicities and not require
corticosteroids.
• Note: A 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 >10Gy) are excluded.
4. Receipt of liver-directed therapies (e.g., RFA, TACE/embolization,
cryotherapy, 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.
5. 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.
6. Non-conventional CS, e.g., clear-cell, mesenchymal, extraskeletal myxoid,
myxoid*, and dedifferentiated CS.
• Note: *Conventional CS with myxoid features are considered Grade 2
conventional CS and are allowed in this study.
7. 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 sponsor for potential inclusion.
8. 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); not requiring steroids; and 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.
9. 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 (e.g., primary biliary cholangitis, autoimmune hepatitis) ), 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 the patients with nonclinically significant
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 non-alcoholic fatty liver disease
(NAFLD) are excluded from the study.
10. 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.
11. 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.
12. Any evidence or history of hepatitis B, hepatitis C, or human
immunodeficiency virus (HIV) infection.
13. 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).
14. Major surgery within 4 weeks prior to this study.
15. Clinically significant bacterial, fungal or viral infection requiring
anti-infective treatment within 2 weeks prior to this study.
16. 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.
17. Any known, documented, or suspected history of illicit substance abuse that
would preclude patient from participation, unless clinically justified (i.e.,
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 its use.
• Note: patients with ongoing or prior history of alcoholism are excluded,
unless they qualify per LFTs and liver imaging.
18. 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
19. 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.