| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060121 |
| E.1.2 | Term | Squamous cell carcinoma of head and neck |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10017758 |
| E.1.2 | Term | Gastric cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To characterize the safety and tolerability and to identify the RP2D of ALKS 4230 administered SC as lead-in monotherapy and in combination with pembrolizumab in subjects with advanced solid tumors (Phase 1)
• To characterize the safety profile of SC ALKS 4230 at the RP2D in combination with pembrolizumab in subjects with advanced solid tumors (Phase 2)
• To estimate the clinical activity of combination treatment with ALKS 4230 and pembrolizumab in terms of overall response rate (ORR) as assessed by Response Evaluation -Criteria in Solid Tumors (RECIST) guidelines version 1.1 separately for
- NSCLC
-Squamous cell carcinoma of the head and neck (SCCHN)
-GEJ cancer
-Ovarian cancer
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| E.2.2 | Secondary objectives of the trial |
- To describe dose-limiting toxicity (DLT) of SC ALKS 4230 as lead-in monotherapy (Phase 1)
- To characterize the PK, clinical (PD) and immunogenicity of SC ALKS 4230 as lead-in monotherapy (Phase 1) and in combination with pembrolizumab (Phase 1 and Phase 2)
- To describe antitumor activity observed with SC ALKS 4230 as lead-in monotherapy and in combination with pembrolizumab (Phase 1)
- To evaluate antitumor efficacy in subjects treated with SC ALKS 4230 in combination with pembrolizumab (Phase 2) |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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.
• NSCLC cohort: subjects with locally advanced unresectable or metastatic NSCLC who have not been previously treated with immune checkpoint inhibitors (CPIs; anti-PD-1, anti-PD-L1, anti-CTLA-4) are eligible; patients who have progressed after other prior systemic therapy are allowed. Patients with EGFR, ALK, ROS1, or other known targetable genomic alterations must have received appropriate targeted treatment and progressed. Eligible patients will have PD-L1 tumor proportion score (TPS) less than 1% as determined by 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.
• 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.
• Ovarian cancer cohort: subjects must have recurrent high-grade serous, endometrioid, or clear cell ovarian, fallopian tube, or primary peritoneal cancer.
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 defined in the protocol
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 10 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 10 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.
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%.
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| E.4 | Principal exclusion criteria |
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 or subjects who are Alkermes or Syneos Health employees directly involved in the conduct of the study.
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.
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
Subjects who developed other autoimmune disorders of Grade ≤3 may enroll if the disorder has resolved and the subject is off steroids for 2 weeks. Subjects who experienced autoimmune colitis as a toxicity of prior immunotherapy must undergo or must have been evaluated by colonoscopy to rule out ongoing inflammation.
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.
11. Subjects known to be positive for human immunodeficiency virus are excluded. Exceptions please see in the protocol.
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.
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, which may interfere with the ability of the subject to cooperate and participate in the study. For more details please see protocol.
16. Subject has received a live vaccine within 30 days of planned start of study therapy. Note: COVID-19 vaccine is allowed (Section 8.4.3)
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. 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. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- The incidence and severity of treatment-emergent adverse events (AEs) (Phase 1 and Phase 2)
- ORR based on RECIST 1.1 (Phase 2)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Treatment-emergent AEs will be evaluated during every visit at the clinic.
Antitumor activity will be determined by the measurement of extent of known disease at baseline and approximately every 9 weeks. After Cycle 10, this should be reduced to every 12 weeks. |
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| E.5.2 | Secondary end point(s) |
-The incidence of DLTs from the beginning of first dose of investigational agent(s) through the end of the DLT observation period (Phase 1)
-Serum concentrations of ALKS 4230 and descriptive PK parameters (Phase 1 and Phase 2)
-Presence of anti-ALKS 4230 antibodies in serum (Phase 1 and Phase 2)
-Numbers of circulating CD8+ T cells, Tregs, and NK cells in peripheral blood (Phase 1 and Phase 2)
-Serum concentrations of IL6 and other cytokines (Phase 1 and Phase 2)
-ORR, Disease Control Rate (DCR), Duration of Response (DOR), Time to Response (TTR), and Progression Free Survival (PFS) per RECIST 1.1 (Phase 1)
-Immune ORR (iORR), immune DCR (iDCR), immune DOR (iDOR), immune TTR (iTTR), and immune PFS (iPFS) per immune RECIST (iRECIST) (Phase 1)
-DCR, DOR, TTR, and PFS, per RECIST 1.1 (Phase 2)
-iORR, iDCR, iDOR, iTTR, and iPFS, per iRECIST (Phase 2)
-Overall survival (OS) (Phase 2)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Serum samples for evaluation of ALKS 4230 PK and patient immunogenicity will be obtained from each subject at predetermined time points.
Antitumor activity will be determined by the measurement of extent of known disease at baseline and approximately every 9 weeks. After Cycle 10, this should be reduced to every 12 weeks. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Korea, Republic of |
| Taiwan |
| United States |
| Netherlands |
| Spain |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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