| 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 | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| 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 | LLT |
| E.1.2 | Classification code | 10027150 |
| E.1.2 | Term | Melanoma malignant |
| 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 | 10067946 |
| E.1.2 | Term | Renal cell carcinoma |
| 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 investigate the safety and tolerability of ALKS 4230 and to determine the maximum tolerated dose and the recommended Phase 2 dose (RP2D) of ALKS 4230 in subjects with advanced solid tumors who are refractory or intolerant to therapies known to provide clinical benefit (Part A)
- To further characterize the safety profile of ALKS 4230 at the RP2D in subjects with melanoma or renal cell carcinoma (RCC) who have received prior therapies known to provide clinical benefit (Part B)
- To characterize the safety profile and antitumor activity of ALKS 4230 administered intravenously (IV) in combination with pembrolizumab in subjects with advanced solid tumors (Part C)
- To describe the dose-limiting toxicity (DLT) of ALKS 4230 (Part A)
- To describe the adverse event (AE) profile of ALKS 4230 (Part A and Part B) |
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| E.2.2 | Secondary objectives of the trial |
- To characterize the clinical pharmacokinetic (PK) profile and immunogenicity of ALKS 4230 alone (Part A and Part B) and in combination with pembrolizumab (Part C)
- To investigate the clinical pharmacodynamic effects of ALKS 4230 alone (Part A and Part B) and in combination with pembrolizumab (Part C)
- To describe any antitumor activity and responses observed with ALKS 4230 (Part A)
- To evaluate the overall response rate (ORR), duration of response (DOR), and time to response for subjects treated with ALKS 4230 in each of the expansion cohorts (Part B) and in combination with pembrolizumab (Part C) |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The subject or the subject’s legal representative is willing and able to provide written informed consent.
2. The subject is aged ≥18 years.
3. For the dose-escalation portion of the study, the subject has a diagnosis of an advanced solid tumor; for the dose-expansion portion of the study (Part B), the subject has a diagnosis of melanoma or RCC.
4. All subjects must have an advanced solid tumor (including lymphomas) that is refractory or, in the judgment of their physician, intolerant to established therapies known to provide clinical benefit for the malignancy in question. Treatment with prior immunotherapy is permitted, with the exception of subjects enrolling in the PD-1/L1 approved tumor types (PD-1/L1 treatment naive) cohort in Part C who are not permitted to have received prior treatment with an anti-PD-1/L1 therapy or prior IL-2 or IL-15 cytokine therapy.
5. Subjects enrolled in the dose-expansion monotherapy part (Part B) or combination therapy part (Part C) of the study must have at least 1 lesion that qualifies as a target lesion based on RECIST.
6. Subjects enrolled in the dose-expansion monotherapy part (Part B) or combination therapy part (Part C) of the study must specifically indicate on the informed consent that he or she agrees to provide archival tumor tissue biopsy sample(s). The archival tumor tissue sample does not have to be obtained prior to enrollment into the study, however every effort should be made to obtained before the subject completes study participation.
7. Subjects enrolled in the combination therapy part (Part C) of the study must have completed the last dose of any broad spectrum antibiotic at least 30 days prior to first dose (Cycle 1, Day 1).
8. Subject is ambulatory with an Eastern Cooperative Oncology Group (ECOG)
performance status of 0 or 1 and an estimated life expectancy of at least 3 months.
9. Subjects must have adequate hematologic reserve as evidenced by:
• Absolute neutrophil count (ANC) 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).
10. Subjects must have adequate hepatic function as evidenced by aspartate transaminase and alanine transaminase values ≤3 × the upper limit of normal (ULN) (≤5 × the 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.
11. Subjects must have adequate renal function as evidenced by a serum creatinine ≤1.5 × the ULN for the reference laboratory or a calculated creatinine clearance of ≥60 mL/min by the Cockroft-Gault equation.
12. Subjects must be recovered from the effects of any previous chemotherapy,
immunotherapy, other prior systemic anticancer therapy, radiotherapy, or surgery (ie, toxicity no worse than Grade 1 [Grade 2 alopecia and treatment-associated peripheral neuropathy are acceptable]).
13. Subjects who have received standard or investigational agents must wait at least 5 half-lives or 4 weeks (whichever is shorter) following prior therapy before enrollment into the study, or 4 weeks if the half-life of the investigational agent is not known.
14. Women of childbearing potential (WOCBP) must have a negative pregnancy test (serum or urine) within 7 days of the start of treatment, and on Day 1 before the first dose is administered. A woman is considered as a WOCBP (fertile) following menarche and until becoming postmenopausal unless permanently sterile. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
15. Meets contraceptive requirements defined in protocol Section 8.4.2. Women of childbearing potential and men (if their sexual partners are WOCBP) must use at least 1 highly effective form of birth control throughout the study. Highly effective methods of birth control include true sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk, in line with the preferred and usual lifestyle of the patient), surgery (bilateral tubal ligation or occlusion, vasectomized partner), progestogen-only or estrogen/progestogen hormonal contraceptive associated with inhibition of ovulation (oral, patch, injectable, implantable, or intravaginal), intrauterine device, or intrauterine hormone-releasing system. See Section 8.4.2 for a definition of WOCBP and a complete description of contraceptive requirements.
In addition to the criteria listed above, to participate in Part C of the study, subjects must meet additional Part C tumor type specific inclusion criteria to enroll into the applicable cohorts. |
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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 with an active infection or with a fever ≥38.5°C (≥101.3°F) within 3 days of the first scheduled day of dosing
3. Subjects with active or symptomatic central nervous system metastases unless the metastases have been treated by surgery and/or radiation therapy, the subject has been tapered to a dose of 10 mg or less of corticosteroids for at least 2 weeks before the first dose, and the subject is neurologically stable
4. Subjects with known hypersensitivity to any components of ALKS 4230
5. Subjects who require pharmacologic doses of corticosteroids (greater than 10 mg of prednisone daily, or equivalent); however, replacement doses, topical, ophthalmologic, and inhalational steroids are permitted. Use of glucocorticoids for the purpose of treating immune-mediated AEs is permitted (see Section 9.8) but may result in discontinuation from study based on consultation between the Investigator and the Medical Monitor. A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
6. Subjects with mean QT interval corrected by the Fridericia Correction Formula values of >470 msec (in females) or >450 msec (in males) following 3 standard 12-lead electrocardiograms (ECGs) conducted approximately 5 minutes apart; 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. Subjects who developed autoimmune disorders while on prior immunotherapy, including 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 ≤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 screening colonoscopy to rule out ongoing inflammation.
8. Subjects with 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; other examples of such conditions would include unstable or poorly controlled hypertension; unstable angina; myocardial infarction, or cardiovascular accident within 6 months of study entry; New York Heart Association Grade 3 or 4 congestive heart failure; chronic obstructive pulmonary disease or diabetes mellitus that has required 2 or more hospitalizations in the last year; severe peripheral vascular disease; or recent serious trauma.
9. Subjects known to be positive for human immunodeficiency virus, hepatitis B or hepatitis C, or active tuberculosis or has a known history of tuberculosis.
10. Subjects who are employed by Alkermes, Syneos Health, the Investigator, the study center (included permanent or temporary contract workers and designees responsible for the conduct of the study), or other affiliate of this study or is immediate family of an employee of Alkermes, Syneos Health, the Investigator, the study center, or other biological or legally adopted.
11. Subjects with known hypersensitivity to any components of pembrolizumab (Part C subjects only)
12. Subjects who have 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 Gleason score <6 with undetectable prostate-specific antigen over the previous 12 months, ductal breast carcinoma in situ with full surgical resection, or treated medullary or papillary thyroid cancer. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- The incidence of DLTs from the first dose through the end of the DLT observation period (Part A)
- The incidence and severity of treatment-emergent AEs according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03) (Part A)
- ORR based on Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.1 (Part B and Part C) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Antitumor activity will be determined by the measurement of extent of known disease at baseline and approximately every 5 to 6 weeks, following each even-numbered treatment cycle. |
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| E.5.2 | Secondary end point(s) |
- The incidence and severity of treatment-emergent AEs according to the National Cancer Institute CTCAE v4.03
- Serum concentrations of ALKS-4230 and descriptive PK parameters using noncompartmental analysis
- Serum concentrations of anti-ALKS-4230 antibodies
- Immune (i-) ORR (iORR) based on Immune RECIST (iRECIST) guidelines
- Disease control rate (DCR) based on RECIST guidelines and immune DCR (iDCR) based on iRECIST guidelines
- DOR based on RECIST guidelines and immune DOR (iDOR) based on iRECIST guidelines
- Progression-free Survival (PFS) for Part B and Part C Cohorts C5, C6, C7 only
- Numbers of circulating CD8 T cells, regulatory T cells, and natural killer cells in peripheral blood
- Serum levels of IL-6 and other cytokines |
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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. |
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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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| Australia |
| Belgium |
| Canada |
| Hungary |
| Korea, Republic of |
| Poland |
| Spain |
| United States |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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