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:
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).
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.
If ≥ 65 years old and not on hormone replacement therapy (HRT), FSH > 30
mIU/mL.
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.
