STOMP OUT: A Phase 2 Study To Evaluate The Effects Of Ivonescimab In Patients With Unresectable/Metastatic Adrenocortical Carcinoma (ACC) Or Unresectable Pheochromocytoma/Paraganglioma (PPGL)

A subject who meets any of the following criteria is ineligible for the study:

1. Received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 4 weeks of the start of the previous cycle or had received previous targeted therapy including small molecular tyrosine kinase inhibitors such as belzutifan, cabozantinib or lenvatinib within 2 weeks before the first dose of study treatment.

3. Major surgical procedures or serious trauma within 4 weeks prior to enrollment or plans for major surgical procedures within 4 weeks after the first dose (as determined by the investigator). Minor local procedures (excluding central venous catheterization and port implantation) within 3 days prior to enrollment.

4. Active autoimmune or lung disease requiring systemic therapy (e.g., with disease modifying drugs, prednisone \>10 mg daily or equivalent, immunosuppressant therapy) within 2 years prior to first dose of study treatment however the following will be allowed:

1. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for thyroid, adrenal or pituitary insufficiency) is permitted.

2. Intermittent use of bronchodilators, inhaled corticosteroids, or local corticosteroid injections is permitted

3. Psoriasis requiring topical treatment only, vitiligo, history of Hashimoto's thyroiditis, Grave's disease, history of radiographic diagnosis of rheumatoid arthritis without active therapy is allowed.

5. Received radionuclide treatment (i.e. I 131 meta-iodo- benzyl guanidine) within 3 months of the first dose of study treatment

6. Receipt of any other type of investigational agent within 28 days before the first dose of study treatment.

7. The subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs.

8. Symptomatic CNS metastases, CNS metastases with hemorrhagic features, CNS metastasis ≥ 1.5 cm, CNS radiation within 7 days prior to randomization, potential need for CNS radiation within the first cycle, or leptomeningeal disease Note: Participants must have stopped corticosteroids or be on physiologic corticosteroid replacement therapy (prednisone ≤ 10 mg daily or equivalent).

9. Live vaccine or live attenuated vaccine within 4 weeks prior to planned first dose of study treatment , or if scheduled to receive a live vaccine or live attenuated vaccine during the study period. Inactivated vaccines are permitted.

10. Severe infection within 4 weeks prior to enrollment, including but not limited to comorbidities requiring hospitalization, sepsis, or severe pneumonia; active infection (as determined by the investigator) requiring systemic anti-infective therapy within 2 weeks prior to randomization (excluding antiviral therapy for hepatitis B or C)

11. Has pre-existing peripheral neuropathy that is ≥ Grade 2 by CTCAE version 6.0

12. Uncontrolled pleural effusions, pericardial effusions, or ascites that is clinically symptomatic Note: Participants managed with indwelling catheters (eg, PleurX) are allowed.

13. History of non-infectious pneumonia requiring systemic corticosteroids, or current interstitial lung disease

14. Active or prior history of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, or chronic diarrhea)

15. Known history of human immunodeficiency virus (HIV) whose viral load is not controlled.

16. Current use of systemic corticosteroids (\>10 mg daily prednisone or equivalent)

17. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation

18. Participants with active hepatitis B are required to have stable or declining levels of hepatitis B DNA by polymerase chain reaction (PCR) on appropriate anti-viral therapy with acceptable tolerability for one month prior to randomization. All participants with active hepatitis C (hepatitis C virus \[HCV\] antibody positive with HCV RNA levels above the lower limit of detection) are excluded.

19. Known allergy to any component of any study drug; known history of severe hypersensitivity to other monoclonal antibodies

20. History or current evidence of any condition (medical \[including adverse events from prior anticancer therapy, disorders secondary to tumor\], surgical or psychiatric \[including substance abuse\]), or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, might lead to higher medical risk and/or is not in the best interest of the participant to participate, in the opinion of the treating investigator

21. Current use of prophylactic or full-dose anticoagulants or anti-platelet agents for therapeutic purposes that is not stable prior to randomization is not allowed. The use of full-dose anticoagulants is permitted as long as the international normalized ratio (INR) or activated partial thromboplastin time (aPTT) is within therapeutic limits according to the medical standard of the enrolling institution

22. The subject has experienced any of the following:

1. clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment

2. hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood within 3 months before the first dose of study treatment

3. any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment

23. Radiographic evidence of cavitating pulmonary lesion(s)

24. Tumor invading or encasing any major blood vessels with the exception of tumor thrombus associated with the primary tumor or located within the renal/adrenal vein or vena cava.

25. Evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of ivonescimab

26. Uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

a. Cardiovascular disorders including i. History of any grade arterial thromboembolic event, Grade 3 and above venous thromboembolic event, as specified in National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 6.0, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy within 12 months prior to first dose of study treatment ii. Congestive heart failure (CHF): New York Heart Association (NYHA) Class II, Class III or Class IV at the time of screening iii. Concurrent uncontrolled hypertension defined as sustained BP \> 150 mm Hg systolic, or \> 100 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment iv. Any history of congenital long QT syndrome v. Any of the following within 12 months before the first dose of study treatment:

* unstable angina pectoris

* clinically-significant cardiac arrhythmias

* stroke (including TIA, or other ischemic event)

* myocardial infarction

* CTCAE grade 3 or higher venous thromboembolism

* Unstable vascular disease (e.g. aortic aneurysm at risk of rupture, Moyamoya disease that required hospitalization) b. Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including: i. Any of the following within 6 months before the first dose of study treatment

* intra-abdominal tumor/metastases invading GI mucosa

* active peptic ulcer disease; participants must be completely recovered

* inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis; participants must be completely recovered from these conditions

* abdominal fistula

* gastrointestinal perforation

* bowel obstruction or gastric outlet obstruction

* intra-abdominal abscess. Note: Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with ivonescimab even if the abscess occurred more than 6 months before the first dose of study treatment. c. Other disorders associated with a high risk of fistula formation including PEG tube placement within 3 months before the first dose of study therapy

27. Pregnant or breastfeeding.

28. A previously identified allergy or hypersensitivity to components of the study treatment formulation.

29. Unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.

30. Evidence within 2 years of the start of study treatment of another malignancy which required systemic treatment except for cured nonmelanoma skin cancer, cured in situ cervical carcinoma, or evidence of localized adenocarcinoma of the prostate Gleason score 6 (3+3) or 7 (3+4 or 4+3) undergoing active surveillance.

31. Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality which, in the judgment of the investigator, would have made the participant inappropriate for entry into this study.

What this study is about