| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adult Patients with Unresectable Stage III or Stage IV Malignant Melanoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced melanoma (stage 3 or 4) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
Phase 2
To establish the Phase 3 dose of indoximod in combination with immune checkpoint inhibitor pembrolizumab or nivolumab in adult patients with unresectable stage III or stage IV malignant melanoma – an open label evaluation of PK, safety and tolerability of the combined treatment.
Phase 3
To evaluate progression-free-survival (PFS) and/or overall survival (OS) in adult patients with unresectable stage III or stage IV malignant melanoma receiving either indoximod plus pembrolizumab or nivolumab versus placebo plus pembrolizumab or nivolumab. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 3
To evaluate the objective response rate (ORR) in adult patients with unresectable stage III or stage IV malignant melanoma receiving either indoximod plus pembrolizumab or nivolumab versus placebo plus pembrolizumab or nivolumab To evaluate safety, tolerability and adverse experience profile of a combination of indoximod and pembrolizumab or nivolumab versus placebo plus pembrolizumab or nivolumab.
To evaluate safety, tolerability and adverse experience profile of a combination of indoximod and pembrolizumab or nivolumab versus placebo plus pembrolizumab or nivolumab.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participant must be 18 years and older (adults and seniors) at the time of signing the
informed consent.
1. Have histologically- or cytologically-confirmed unresectable stage III or stage IV melanoma, as per AJCC (8th Edition) staging system not amenable to local therapy
2. Subject must have at least one radiologically measurable lesion as per RECIST 1.1 (Appendix 7: RECIST 1.1 Guideline of the protocol) defined as a lesion that is 10mm in longest diameter or lymph node that is 15mm in short axis imaged by computed tomography (CT) scan or magnetic resonance imaging (MRI).
3. Have been untreated for advanced or metastatic disease except as follows
a) BRAF V600 mutant melanoma may have received standard of care targeted therapy (e.g. BRAF/MEK inhibitor, alone or in combination)
b) Prior adjuvant or neoadjuvant melanoma therapy is permitted if it was completed at least 4 weeks before randomization and all related adverse events have either returned to baseline or stabilized for non-immune therapy based regimens.
c) Prior adjuvant therapy containing immunotherapy such as interferon or anti-CTLA-4 therapy will only be permitted if relapse did not occur during treatment or within 6 months of treatment discontinuation.
d) Prior anti-PD-1, anti-PD-L1, or IDO1 inhibitors are excluded.
4. Have documentation of V600-activating BRAF mutation status or consent to BRAF V600 mutation testing during the screening period.
5. Must collect and submit available archival tumor tissue. If no archival tumor tissue is available, subject will not be excluded.
6. ECOG performance status 0 or 1
7. Patient has adequate bone marrow and organ function as defined by the following laboratory values: Absolute Neutrophil Count (ANC) ≥ 1,500 cells/μL (1.5 x109/L), without growth factor support; Platelets ≥ 100,000 cells/μL (100 x109 cells/L), without growth factor support; Hemoglobin ≥ 9.0 g/dL (90g/L); INR ≤ 2 x ULN
8. Any hyperkalemia, hypokalemia, hypermagnesemia, hypomagnesemia, hypercalcemia, hypocalcemia must be ≤ Grade 1 per CTCAE Version 4.03
9. Serum Creatinine ≤ 1.5 x ULN, or creatinine clearance (Ccr) > 60 mL/min based on the Cockcroft-Gault equation.
10. Total bilirubin, amylase and lipase ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, total bilirubin ≤ 3 x ULN, with direct bilirubin ≤ 1.5 x ULN)
11. Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) ≤ 3 x ULN, (in subjects with liver metastases, < 5 x ULN)
12. Serum Albumin ≥ 3 g/dL
13. Patients must have normal pituitary function as determined by investigator clinical judgment.
14. HIV positive patients who are stable on antiretroviral medication (ART). Patients stable on ART are defined as those who have received ART for at least 1 year with no adverse drug reactions requiring regular monitoring, no current illnesses or pregnancy, a good understanding of lifelong adherence, and evidence of treatment success. Treatment success is defined as two consecutive undetectable viral load measures or, in the absence of viral load monitoring, rising CD4 counts or CD4 counts above 200 cells/mm3 and an objective
adherence measure.
15. Patients with known brain metastases will only be eligible after definitive treatment of brain metastases with SBRT or surgery provided that the brain lesions are stable (without evidence of progression by imaging for at least 4 weeks before the first dose of study treatment), subject is neurologically stable and has had no persistent side effects / complications from the treatment, have no evidence of new or enlarging brain metastases confirmed by repeat imaging, and have not required steroids for at least 14 days before
study treatment.
16. If female of childbearing potential, must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. If female of childbearing potential, must be willing to use an adequate method of contraception as outlined in Appendix 4, for the course of the study through minimum of 4 months (for those who receive pembrolizumab) and a minimum of 5 months (for those
who receive nivolumab) after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
17. If male of childbearing potential, must agree to use an adequate method of contraception as outlined in Appendix 4, and not to donate sperm starting with the first dose of study therapy through minimum of 4 months (for those who receive pembrolizumab) and a minimum of 5 months (for those who receive nivolumab) after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
18. Ability to ingest oral medications
19. Ability to understand and the willingness to sign a written informed consent document |
|
| E.4 | Principal exclusion criteria |
1. Has Ocular Melanoma
2. Has received prior systemic treatment for unresectable or metastatic melanoma (except
BRAF directed therapy as noted in inclusion criteria #3).
3. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
IDO1 inhibitor or any other antibody or drug specifically targeting checkpoint pathways
other than anti-CTLA-4 which is permitted in the adjuvant setting.
4. Has received prior adjuvant therapy, monoclonal antibody or an investigational agent or
device within 4 weeks or 5 half-lives (whichever is longer) before study Day 1 or not
recovered (Grade 1 or at baseline) from AEs due to previously administered agents.
Exception to this rule would be use of bisphosphonates, which is not excluded.
5. Has received prior radiotherapy within 2 weeks of therapy. Subjects must have recovered
from all radiation-related toxicities, not require corticosteroids, and not have had radiation
pneumonitis. A 1-week washout is permitted for palliative radiation (2 weeks of RT) to
non-CNS disease.
6. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days before the first dose of study treatment.
7. Has known active, uncontrolled brain or CNS metastases and/or carcinomatous meningitis.
8. History or presence of an abnormal electrocardiogram (ECG) that, in the investigator’s
opinion, is clinically meaningful. Screening QTc interval > 480 msec is excluded
(corrected by Fredericia or Bazett formula). In the event that a single QTc is > 480 msecs,
the subject may enroll if the average QTc for the 3 ECGs is < 480 msecs.
9. Has clinically significant cardiac disease, including unstable angina, acute myocardial
infarction within 6 months from first dose of study drug administration, New York Heart
Association Class III or IV congestion heart failure (see Appendix 6), and arrhythmia
requiring therapy. Medically controlled arrhythmia would be permitted.
10. Has history of allergic reactions attributed to compounds of similar chemical or biologic
composition to pembrolizumab, nivolumab or tryptophan-containing substances.
11. Is pregnant or breast-feeding or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through minimum of
4 months (for those who receive pembrolizumab) and a minimum of 5 months (for those
who receive nivolumab) after the last dose of study treatment.
12. Patients who have active, chronic, or on active treatment for Hep B or Hep C are excluded.
13. Any other cancer, unless the patient has been disease-free for ≥ 5 years (except treated and
cured basal-cell or squamous-cell skin cancer, superficial bladder cancer, or treated
carcinoma in situ of the cervix, breast, or bladder and treated localized prostate cancer with
undetectable PSA for 2 years).
14. Patients with laboratory evidence of pancreatitis are excluded.
15. Has presence of a gastrointestinal condition that may affect drug absorption.
16. Patients with an active autoimmune disease that has required systemic treatment in past 2
years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of
systemic treatment.
17. Chronic use of immune-suppressive drugs (i.e., systemic corticosteroids used in the
management of cancer or non-cancer related illnesses, e.g., COPD in dosing exceeding 10
mg daily of prednisone equivalent). Inhaled steroids are allowed.
18. Patients who are receiving or have received any other investigational agent within 30 days
prior to enrollment into the study (or 5 half-lives of agent, whichever is longer).
19. Patients taking L- tryptophan or 5-hydroxy-tryptophan supplements.
20. Patients with untreated or uncontrolled HIV |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The co-primary efficacy endpoints below will be analyzed using ITT and the PPS:
1. Progression-free survival (PFS) time which is defined as time from date of randomization until the earliest date of disease progression per RECIST 1.1, or death from any cause, whichever comes first. Patients who have neither progressed nor died will be censored at the last tumor assessment date for the endpoint PFS and will be assessed per RECIST 1.1.
2. OS is defined as the time from the date of randomization until death from any cause. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Disease progression and survival |
|
| E.5.2 | Secondary end point(s) |
The following secondary efficacy endpoint will be analyzed using ITT and the
PPS:
- Objective response rate (ORR): The first tumor assessment test will be conducted at 9 weeks followed by assessments every 9 weeks for duration of study participation. Defined as patients who have a best response as complete or partial response based on RECIST 1.1.
An overall false-positive rate of 5% level for the above key secondary efficacy endpoint will be maintained, in that no significance of the key secondary endpoint will be claimed unless either of the co-primary statistical analyses is significant at the 2.5% level. We will compare response rates in the study groups using the
stratified Miettinen and Nurminen method (1985). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 52 |
| 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 |
| France |
| Germany |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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