A Study of Oral 7HP349 (Alintegimod) in Combination With Ipilimumab Followed by Nivolumab Monotherapy

A Phase 1b/2a Multi-Center, Dose Escalation and Reference Regimen-Controlled, Multi-Cohort Study to Determine the Safety and Efficacy of Oral 7HP349 (Alintegimod) in Combination With Ipilimumab Followed by Nivolumab Monotherapy in Patients With Locally Advanced or Metastatic Cancers Following One or More Prior Therapies

This study is an open-label Phase Ib (Part A) dose escalation followed by a blinded, randomized, multi cohort Phase 2a (Part B) comparison of combination vs. reference regimens.

Currently study will only be enrolling the Phase 1b and the Phase 2a protocol requirements will be added to the study near completion of the Phase 1b

This Phase study is designed to evaluate the safety, tolerability, and preliminary efficacy of oral Alintegimod (Alintegimod) alone, and then in combination with ipilimumab for, followed by nivolumab monotherapy cycles. All patients will receive nivolumab after completion of treatment with Alintegimod plus ipilimumab combination therapy to continue nivolumab treatment until the end of study (12 months) unless progression or toxicity result in early termination.

Inclusion and Exclusion Criteria for Phase 1b

Inclusion Criteria

1. Adult patients (age 18 or older)

2. Patient has a histologically confirmed diagnosis of any of the following locally advanced or metastatic solid tumors: melanoma, pleural mesothelioma, renal cell carcinoma, MSI-high or mismatch repair-deficient colorectal cancer, hepatocellular carcinoma, and non-small cell lung cancer with no EGFR or anaplastic lymphoma kinase (ALK) genomic tumor aberrations, or tumor types for which the combination of ipilimumab and nivolumab has been FDA approved. Patients may have received treatment with anti PD-1/PD-L1.

3. ANC ≥ 1000/µL without use of G-CSF, Hgb ≥ 9 g/dL without required blood transfusion for at least 5 days prior to pretreatment baseline, and platelet count ≥ 75,000/µL without transfusions for at least 5 days prior to pretreatment baseline.

4. ECOG performance status of 0 or 1.

5. Has a life expectancy of > 12 weeks.

6. Renal and hepatic function requirements:

   • a. Renal function with either an eCrCL ≥ 60 mL/min (modified Cockcroft-Gault) or eGFR ≥ 60 mL/min/1.73 m2 (using MDRD or CKD-EPI or similar equations).
   • b. Hepatic function with ALT/AST ≤ 3 x ULN, total bilirubin ≤ 1.5 x ULN (except for patients with Gilbert Syndrome). If patients have hepatic metastases, then AST/ALT≤ 5 x ULN will be allowed.

7. Men receiving the investigational drug and are sexually active with women of child-bearing potential (WCBP) must use contraception during treatment and for 5 half-lives after the last dose of the investigational drug or Women, not otherwise meeting other exclusion criteria, who are WCBP must be on contraception for a minimum duration of 3 months prior to treatment and continue contraception during treatment and for 5 half-lives after the last dose of the investigational drug.

8. All Grade 3 AEs related to prior therapies have returned to Grade 1 or resolved to baseline (this includes with appropriate therapy in the case of thyroid dysfunction).

9. All patients must have measurable disease by applicable RECIST criteria.

10. Willing to allow blood samples to be used for research.

Exclusion Criteria:

1. Patients must not have received prior anticancer therapy or radiation therapy within the 3 weeks and must not have undergone major surgery within 4 weeks prior to initiation of treatment on protocol. Palliative radiation therapy is allowed. For small molecules (MW < 0.9 kDA), the washout period is 3 weeks or 5 half-lives, whatever comes first.

2. Active brain metastasis or leptomeningeal disease. Patients with treated brain metastasis must have stable disease, evidenced by MRI brain imaging for at least 4 weeks, and the patient must have been off steroids for at least 2 weeks prior to first dose of study drug.

3. Previous episodes of ≥ Grade 3 (G3) immune-related toxicity that includes G3 colitis, G3 pneumonitis, G3 skin rash, G3 increase in liver enzymes (with the exception of symptoms that in the opinion of the investigator will not compromise the patients' safety on the trial. Patients with stable endocrinological AEs (e.g., hypothyroidism, adrenal insufficiency, hypopituitarism, or diabetes mellitus) are allowed.

4. Persistent toxicity of NCI CTCAE version 5 Grade > 1 severity that is related to prior therapy.

   Note: Sensory neuropathy, hypothyroidism or alopecia of Grade ≤ 2 are acceptable. Other Grade 2 toxicities of prior treatments that are controlled with medication (e.g., diabetes or hypertension) are permitted.

5. Concurrent administration of medications or foods that are strong inhibitors or inducers of cytochrome p450 3A (CYP3A) within 2 weeks before study intervention. Alintegimod may increase exposure to CYP3A4 substrates; consider a dose reduction of such substrates and monitor for signs of toxicities of co-administered sensitive CYP3A substrates (see listing of strong inhibitors and inducer drugs in FDA tables). An alternative is to replace such agents with drugs that are not CYP3A4 metabolized if at all feasible.

6. The patient has cardiac conditions as follows:

   • a) myocarditis;
   • b) uncontrolled hypertension (blood pressure > 160/100) despite optimal therapy;
   • c) uncontrolled angina; ventricular arrhythmias; congestive heart failure (New York Heart Association Class II or above);
   • d) prior or current cardiomyopathy;
   • e) uncontrolled atrial fibrillation with heart rate > 100 beats per minute (bpm); unstable ischemic heart disease (myocardial infarction within 6 months prior to starting treatment or angina requiring use of nitrates more than once weekly);
   • f) concomitant medication with drugs known to cause Torsades de Pointes;87
   • g) QT interval correction for heart rate using Fridericia's formula (QTcF) ≥ 470 ms (average from 3 QTcF values on the triplicate 12-lead electrocardiogram [ECG]) at screening.

7. Known history of a positive test for HIV, or positive test for hepatitis B (positive for HBsAg) or hepatitis C (HCV RNA).

8. Concurrent malignancies are permitted if they were previously treated, and all treatment of that malignancy was completed at least 2 years before enrollment and no evidence of disease exists, or with agreement from the Principal Investigator (PI), patients who have a concurrent malignancy that is clinically stable and does not require tumor-directed treatment are eligible to participate if the risk of the prior malignancy interfering with either safety or efficacy endpoints is very low, or with agreement from the PI, other malignancies may be permitted if the risk of the prior malignancy interfering with either safety or efficacy end points is very low. Adequately treated basal or squamous cell carcinoma or carcinoma in situ is allowed.

9. Men receiving the investigational drug and are sexually active with women of child-bearing potential (WOCBP) must use contraception during treatment and for 5 half-lives after the last dose of the investigational drug or Women, not otherwise meeting other exclusion criteria, who are WOCBP must be on contraception for a minimum duration of 3 months prior to treatment and continue contraception during treatment and for 5 half-lives after the last dose of the investigational drug.

10. The patient has concurrent severe and/or uncontrolled medical disease that could compromise participation in the study (i.e., uncontrolled diabetes, severe infection requiring active treatment, severe malnutrition, chronic severe liver or renal disease).

11. Use of corticosteroids or other immunosuppressive medication, current or within 14 days of administration of Alintegimod with the following exceptions:

    • a) Topical, intranasal, inhaled, ocular, intra-articular corticosteroids;
    • b) Physiological doses of replacement corticosteroids (e.g., for adrenal insufficiency) are not to exceed 10 mg/day of prednisone or equivalent.
    • c) Corticosteroid premedication for infusion and/or hypersensitivity reactions.
    • d) Patients may be treated with a short (<24h) pulse course of corticosteroids to mitigate infusion or hypersensitivity reactions to radiocontrast agents.

12. Receipt of live attenuated vaccine within 28 days of the first dose of Alintegimod.

13. Serious autoimmune disease at the discretion of the treating Investigator: patients with a history of active serious inflammatory bowel disease (including Crohn's disease and ulcerative colitis) and autoimmune disorders such as rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus or autoimmune vasculitis (e.g., Wegener's Granulomatosis) are excluded from participation in this study

14. Active or history of pneumonitis (drug-induced), idiopathic pulmonary fibrosis, Interstitial Lung Disease (ILD), or lung disease that may interfere with assessment of pneumonitis. History of radiation pneumonitis in a previous radiation field is permitted.

15. Previous participation in a study of any investigational agent within 21 days of enrollment or within 5 half-lives of the study treatment, whichever is the least.

16. Use of mechanical ventilation or having a resting O2 saturation < 90% (on room air) by pulse-oximetry, require renal dialysis, require vasopressors, and/or severe hepatic sinusoidal obstruction syndrome.

17. Proven or suspected ongoing systemic infection requiring IV antibiotics.

18. Women who are pregnant or lactating.

    Note: Women of childbearing potential (WOCBP) must have a "negative" serum pregnancy test within 1 week prior to treatment. Non-childbearing potential is defined as 1 of the following:

    • a) Postmenopausal with > 1 year since last menses and:
    • 1. If ≥ 65 years old, follicle-stimulating hormone (FSH) > 40 mIU/mL.
    • 2. If ≥ 65 years old and not on hormone replacement therapy (HRT), FSH > 30 mIU/mL.
    • 3. If ≥ 65 years old and on HRT, the FSH requirement is not applicable. Postmenopausal females on HRT will be allowed if HRT has been stable for ≥ 6 months prior to dosing of study drug(s).
    • b) Written medical documentation of being sterilized (e.g., hysterectomy, double oophorectomy, bilateral salpingectomy) with the procedure performed ≥ 6 months prior to dosing study drug(s).

    Note: Tubal ligation is not considered a form of permanent sterilization.

19. Psychiatric illness/social circumstances that would limit compliance with study requirements and substantially increase the risk of adverse events or have compromised ability to provide written informed consent.

20. Patients who have had allogeneic tissue or solid organ transplantation. Prior T cell therapy is allowed

21. Use of biotin (i.e., Vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 µg (NIH-ODS 2022; Section 5.9.2.1).

    Note: Patients who switch from a high dose to a dose of ≤30 µg/day are eligible for study entry.

22. Any condition that is in the opinion of the investigator may compromise patient's participation in the trial.

23. Active peptic ulcer disease or gastritis, active diverticulitis, or other serious gastrointestinal disease associated with diarrhea within the past 2 years before the start of therapy or GI disease which affects oral drug absorption.

24. Patients with known soy allergy.