A Phase 1/2 Study of ALKS 4230 Administered Subcutaneously as Monotherapy and in Combination With Pembrolizumab in Subjects With Advanced Solid Tumors - ARTISTRY-2 (001)

1. Subject is aged >=18 years.
2. Subject or the subject*s legal representative provides written informed
consent.
3. For Phase 1, subject must have an advanced solid tumor and progressive
disease following at least one line of therapy.
4. For Phase 2, subject must have one of the following tumor types or specific
histology:
• SCCHN cohort: subjects with regionally advanced and/or distantly metastatic
head and neck squamous cell carcinoma of non-cutaneous origin that has relapsed
or failed to achieve complete response after at least one line of systemic
therapy given alone or in combination with surgery and /or radiation therapy,
and that has failed to achieve complete response or relapsed after (or subject
has become intolerant to) CPI (given alone or in combination with other
agents), and that is presently considered inoperable and unamenable to (re-)
irradiation.
• Gastric/GEJ cohort: subjects with unresectable metastatic or locally advanced
gastric
or GEJ adenocarcinoma who have not been previously treated with immune CPIs
(anti-PD-1, anti-PD-L1, anti-CTLA-4) and who have progressed on and/or after two
prior regimens. Prior regimens had to have included a fluoropyrimidine and a
platinum chemotherapy. Progression within 6 months of prior adjuvant or
neoadjuvant chemotherapy will be deemed a rapid progressor and thus equivalent
to
one advanced/metastatic disease treatment regimen. Changing from IV to oral
fluoropyrimidine without noted progression is considered only one prior regimen.
Her2 positive patients must have received prior anti-Her2 therapy and
demonstrate
progressive disease. PD-L1 status must be known at the time of enrollment based
on
an approved test. If PD-L1 status is unknown during Screening, tumor tissue
(fresh
biopsy or archived samples) must be tested for PD-L1 expression prior to
enrollment. Patients with known MSI-high/dMMR status are not eligible.
• Ovarian cancer cohort: subjects must have recurrent high-grade serous,
endometrioid, or clear cell ovarian, fallopian tube, or primary peritoneal
cancer. Subject must have experienced a response lasting at least 3 months to
first-line platinum-based therapy but must be considered resistant to the last
administered platinum containing therapeutic regimen. Subjects must have
received prior monoclonal antibody that inhibits angiogenesis (e.g.,
bevacizumab) either as single agent or in combination or be deemed ineligible
or intolerant. Subject with a known BRCA-1 or -2 mutation must have received
prior poly ADP ribose polymerase (PARP) inhibitor. Subject must not have
received prior checkpoint inhibitor therapy.
5. Subject must have at least one target lesion based on RECIST.
6. Subject has an Eastern Cooperative Oncology Group Performance Status (ECOG
PS) score of 0 or 1 and an estimated life expectancy of at least 3 months.
7. Subject has adequate hematologic reserves, measured within 7 days prior to
start of study treatment, as evidenced by:
• Absolute neutrophil count of >=1000/µL,
• Absolute lymphocyte count of >=500/µL,
• Platelet count of >=75,000/µL, and
• Hemoglobin of >=9 g/dL (subjects may be transfused to this level if necessary).
8. Subject has adequate hepatic function as evidenced by aspartate transaminase
and alanine aminotransferase values <=3 × the upper limit of normal (ULN) (<=5 ×
ULN if the liver is known to be involved by metastatic disease) and serum total
bilirubin values of <=1.5 × ULN (<=2 × ULN for subjects with known Gilbert*s
syndrome) for the reference laboratory measured within 7 days prior to start of
study treatment.
9. Subject has adequate renal function as evidenced by a serum creatinine <=1.5
× ULN for the reference laboratory or a calculated creatinine clearance of >=45
mL/min by the Cockcroft-Gault equation measured within 7 days prior to start of
study treatment.
10. Subject has recovered from the effects of any prior chemotherapy,
immunotherapy, other prior systemic anticancer therapy, radiotherapy, or
surgery (ie, toxicity no worse than Grade 1 [any grade alopecia and treatment
associated peripheral neuropathy are acceptable]).
11. Subject who has received standard or investigational antineoplastic agents
must wait at least 5 half lives or 4 weeks, whichever is shorter, before
enrollment into the study or 4 weeks if the half life of the investigational
agent is not known. Subjects may be enrolled within 3 weeks of previous
treatment upon agreement between Medical Monitor and Principal Investigator.
12. Women of childbearing potential (WOCBP) must have a negative pregnancy test
(serum or urine) within.3 days before the first dose of study drug (see the
protocol for the definition of WOCBP).
13. Subject agrees to abide by the contraceptive requirements detailed in the
protocol.
14. Subject has international normalized ratio (INR) AND/OR prothrombin time
(PT) AND activated partial thromboplastin time (aPTT) <=1.5× ULN unless the
subject is receiving anticoagulant therapy, in which case INR and/or PT and
aPTT must be within desired therapeutic range of intended use for such
anticoagulants.
15. Subjects enrolled in the dose expansion part of the study (Phase 2) must
agree to provide archival tumor tissue biopsy sample(s) if available.
16. For subjects with underlying chronic lung disease, and/or lung primary or
metastatic disease, and/or pleural effusions, room air oxygen saturation must
be >=92%.

1. Subject is currently pregnant or breastfeeding or is planning to become
pregnant during the study period.
2. Subjects who are investigational site staff members directly involved in the
conduct of the trial and their immediate family members, site staff members
otherwise supervised by the Investigator, or subjects who are Alkermes or
Syneos Health employees directly involved in the conduct of the study
(immediate family is defined as a spouse, parent, child, or sibling, whether
biological or legally adopted).
3. Subject has an active infection or a fever >=38.5°C (>=101°F) within 3 days of
the first scheduled day of dosing for the monotherapy lead-in of Phase 1 or
Cycle 1 of Phase 2.
4. Subjects who have received therapeutic systemic antibiotics within 14 days
prior to starting investigational therapy excluded unless specifically exempted
on a case-by-case basis by the Medical Monitor. Antibiotics given for
peri-procedural prophylaxis or given presumptively for a limited time (e.g.,
until infection was ruled out), as well as topical or intra-ocular antibiotics,
shall not be exclusionary.
5. Subject has known hypersensitivity (Grade >=3) to any components of ALKS
4230, to pembrolizumab, or any of its excipients.
6. Subjects with mean QT interval corrected by the Fridericia Correction
Formula values of >470 msec (in females) or >450 msec (in males) following a
standard 12-lead electrocardiogram (ECG); subjects who are known to have
congenital prolonged QT syndromes; or subjects who are on medications known to
cause prolonged QT interval on ECG.
7. Subject has developed Grade >=3 autoimmune disorders while on prior
immunotherapy, (e.g., pneumonitis, nephritis, and neuropathy). Subjects who
have immune-mediated endocrinopathies and are stable on hormone replacement
therapy are not excluded. Subjects who developed other autoimmune disorders of
Grade <=2 may enroll if the disorder has resolved and the subject is off
systemic steroids for >=28 days. Subjects who experienced autoimmune colitis as
a toxicity of prior immunotherapy must undergo colonoscopy to rule out ongoing
inflammation. Vitiligo is not exclusionary.
8. Subjects who have received radiotherapy within the last 4 weeks before start
of study treatment, with the exception of limited field palliative radiotherapy
that has been completed at least 2 weeks before starting study treatment.
9. Subject has active or symptomatic central nervous system metastases unless
the metastases have been treated by surgery and/or radiation therapy, and/or
gamma knife, the subject has been tapered to a dose of 10 mg of prednisone (or
equivalent) or less of corticosteroids for at least 2 weeks before the first
dose of study agent(s), and the subject is neurologically stable.Patients with
history of brain metastases or a suspicion of brain metastases must have a
brain magnetic resonance imaging (MRI) at baseline.
10. Subject has an active autoimmune disease that has required systemic
treatment within the past 3 months or a documented history of clinically severe
autoimmune disease that has required systemic steroids and/or immunosuppressive
agents. Limited exceptions may be granted on a case-by-case basis by the
Medical Monitor. Replacement therapy (eg, thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency) is
not considered a form of systemic treatment and is allowed.
11. Subjects known to be positive for human immunodeficiency virus are
excluded. Subject with active hepatitis B (eg, hepatitis B surface antigen
[HBsAg] reactive) are excluded, however, a subject with past hepatitis B virus
(HBV) infection or resolved HBV infection (defined as the presence of hepatitis
B core antibody [HBcAb] and absence of HBsAg) may be enrolled provided that HBV
DNA is negative. Subjects with active hepatitis C (eg, hepatitis C virus [HCV]
ribonucleic acid [RNA] [qualitative] are detected) is excluded, however, a
subject with cured hepatitis C (negative HCV RNA status) may be enrolled.
12. Subjects with active tuberculosis or a known history of tuberculosis are
excluded.
13. Subjects requiring pharmacologic doses of systemic corticosteroids (greater
than 10 mg of prednisone daily, or equivalent) are excluded; however,
replacement doses, topical, ophthalmologic, inhalational intra-articular, and
epidural corticosteroids are permitted.
14. Subject has had a second malignancy within the previous 3 years. This
criterion does not apply to subjects with an adequately treated basal cell or
squamous cell skin cancer, carcinoma in situ of the cervix, prostate cancer of
highest Gleason score <=6 with undetectable prostate-specific antigen (PSA) over
the previous 12 months, breast carcinoma in situ with full surgical resection.
15. Subject has any other concurrent uncontrolled illness, including mental
illness or substance abuse disorder, which may interfere with the ability of
the subject to cooperate and participate in the study. Other examples of such
conditions would include unstable, poorly controlled, or severe hypertension;
clinically significant pericardial effusion; New York Heart Association Class
III or IV (see Appendix 1: New York Heart Association Heart Disease
Classifications) congestive heart failure; known cardiopulmonary disease,
defined as unstable angina, myocardial infarction, or cerebrovascular accident
within 6 months of first dose; chronic obstructive pulmonary disease or
diabetes mellitus that has required two or more hospitalizations in the last
year; severe peripheral vascular disease; or recent serious trauma.
16. Subject has received a live vaccine within 30 days of planned start of
study therapy. Seasonal influenza vaccines for injection are generally
inactivated flu vaccines and are allowed; however, intranasal influenza
vaccines (eg, Flu-Mist®) are live attenuated vaccines and are not allowed.Note:
COVID-19 vaccine is allowed.
17. Subject has taken immunosuppressive medication within 14 days of planned
start of study therapy.
18. Subject has active uncontrolled coagulopathy.
19. Subjects with dyspnea at rest or requiring oxygen therapy.
20. Prior solid organ and/or non-autologous hematopoietic stem cell or bone
marrow transplant recipients.
21. Subjects who have received prior IL-2-based or IL-15-based cytokine
therapy.