Overview
This is a phase 3 study to compare the efficacy and safety of HBI-8000 or Placebo combined with nivolumab on patients with unresectable or metastatic melanoma and eligible patients who are not adolescents or patients with new, progressive brain metastasis will be stratified by PD-L1 expression and LDH level.
Description
This is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study of HBI-8000 or Placebo combined with nivolumab. Randomization of eligible patients will be stratified by PD-L1 expression (positive, ≥1% expression level versus negative, <1% expression level) and LDH (normal versus elevated) in the main study. Adults with new, progressive brain metastasis, or adolescents with or without new progressive brain metastasis will be enrolled in a separate, non-randomized, open-label cohort to receive the combination of HBI-8000 and nivolumab.
In the main study, eligible patients will be randomized within the appropriate stratum at a 1:1 ratio to the Test arm or the Control arm. Study treatment will be initiated within 3 days of randomization.
A treatment cycle consists of 28 days. Patients will be treated with one of the following:
Test arm: HBI-8000 30 mg oral BIW + nivolumab IV at specific doses on specific days
Control arm: Placebo oral BIW + nivolumab IV at specific doses on specific days
The Study Treatment (HBI-8000 or Placebo) is administered approximately 30 minutes after a full meal.
The Study Treatment (HBI-8000 or Placebo) will be administered twice a week on the following days of every 28-day cycle:
- CxW1: Days 1, 4
- CxW2: Days 8, 11
- CxW3: Days 15, 18
- CxW4: Days 22, 25
Study treatment must commence within 3 days after randomization and continue up to 2 years or until disease progression (confirmed), unacceptable toxicity or patient withdrawal of consent.
In addition to Study Treatment, nivolumab is administered at specific doses on specific days as an intravenous infusion over approximately 30 minutes. Nivolumab will be administered on Day 1 of each cycle.
For non-randomized cohort for special population, eligible subjects will receive HBI-8000 30 mg oral BIW and nivolumab IV at specific doses on specific days, under the same schedule as described above. For adolescents weighing < 40 kg, nivolumab will be dosed at specific doses every 4 weeks. Nivolumab will be administered on Day 1 of each cycle.
Eligibility
Inclusion Criteria:
- Histopathologically confirmed diagnosis of non-uveal, Stage III (unresectable), or Stage IV (metastatic) melanoma according to AJCC staging system (8th edition).
- Known BRAF V600 mutation status or consent to BRAF V600 mutation testing before randomization.
- Tumor tissue available for PD-L1 testing at central lab. PD-L1 expression level is
required for randomization. In order to be randomized, a patient must be classified as
PD-L1 positive or PD-L1 negative according to the following criteria:
- PD-L1 positive (≥ 1% tumor cell membrane staining in a minimum of a hundred evaluable tumor cells) vs
- PD-L1 negative (< 1% tumor cell membrane staining in a minimum of a hundred evaluable tumor cells).
Note: If an insufficient amount of tumor tissue from an unresectable or metastatic
site is available prior to the start of the Screening Phase, patients must consent to
allow the acquisition of additional tumor tissue for assessment of the biomarker.
4. Males or females 12 years of age or older.
5. ECOG performance status ≤1 for age ≥18 years, Lansky performance score ≥80% for age 12
to 17 years.
6. At least one measurable lesion defined by RECIST 1.1 criteria, (separate from the
lesion to be used for tumor tissue collection for PD-L1 testing) not counting brain
metastasis with:
- Longest diameter ≥10 mm by CT (when slice thickness is ≤5 mm); or ≥ 2× slice
thickness (when slice thickness is >5 mm)
- Pathologically enlarged lymph node: ≥15 mm in short axis by CT (when slice
thickness is ≤5 mm)
- Clinical: ≥10 mm (that can be accurately measured with calipers).
7. Have not received anti-PD-1, anti-PD-L1 or other systemic therapy for unresectable or
metastatic melanoma, except for the following, provided that the patient has recovered
from all treatment-related toxicities:
- BRAF mutation targeting therapy > 4 weeks before administration of Study
Treatment.
- Adjuvant or neoadjuvant therapy with PD-1 or PD-L1 inhibitors or anti-CTLA-4) is
allowed if disease progression/or recurrence occurred at least 6 months after the
last dose and no clinically significant immune related toxicities leading to
treatment discontinuation were observed
- Adjuvant interferon therapy must have been completed > 6 weeks before
administration of Study Treatment
8. Any prior radiotherapy or minor surgery must be completed at least 2 weeks and 1 week
respectively before Day 1 dosing and recovered from all treatment related toxicities
9. Screening laboratory results within 14 days prior to randomization:
- Hematology: WBC ≥3000/μL, neutrophils ≥1500/μL, platelets ≥100 × 103/μL,
hemoglobin ≥10.0 g/dL independent of transfusion. The use of erythropoietic
growth factor to achieve hemoglobin (Hgb) ≥ 10 g/dl is acceptable.
- The CrCL≥ 30 mL/min using Cockcroft-Gault formula.
- AST and ALT ≤3 × ULN, alkaline phosphatase ≤2.5 × ULN unless bone metastases
present (patients with documented bone metastases: alkaline phosphatase <5 x
ULN), bilirubin ≤ 1.5 × ULN (unless known Gilbert's disease where it must be ≤ 3
× ULN), serum albumin ≥ 3.0 g/dL).
10. Negative serum pregnancy test at baseline for women of childbearing potential.
11. Females of childbearing potential (non-surgically sterile or premenopausal female
capable of becoming pregnant) and all males (due to potential risk of drug exposure
through the ejaculate) must agree to use adequate birth control measures from study
start, during the study and for 5 months after the last dose of Study Drug. Acceptable
methods of birth control in this trial include two highly effective methods of birth
control (as determined by the Investigator; one of the methods must be a barrier
technique) or abstinence.
12. Have the ability to understand and the willingness to sign a written informed consent
document, comply with study scheduled treatment, visits and assessments.
Exclusion Criteria:
1. History of ≥ Grade 3 hypersensitivity reactions to monoclonal antibodies.
2. Previous treatment with a PD-1, PD-L1, PD-L2, CTLA-4 inhibitor, or any other agents
targeting T-cell co-stimulation or immune checkpoint pathways for unresectable or
metastatic melanoma.
3. History of a cardiovascular illness including: congestive heart failure (New York
Heart Association Grade III or IV); unstable angina or myocardial infarction within
the previous 6 months; or symptomatic cardiac arrhythmia despite medical management.
QT interval corrected by heart rate using QTcF >450 ms in males or >470 ms in females,
or congenital long QT syndrome.
4. Uncontrolled hypertension, systolic blood pressure (SBP) >160 mmHg or diastolic blood
pressure (DBP) >100 mmHg.
5. Patients with new, active, or progressive brain metastases or leptomeningeal disease
with except when considered for a separate special open-label cohort described in
protocol Section 5.3 or "Inclusion of Patients with Progressive Brain Metastasis"
section in the protocol synopsis.
6. History of hemorrhagic diarrhea, inflammatory bowel disease, active uncontrolled
peptic ulcer, or bowel resection that affects absorption of orally administered drugs.
7. Active, known, or suspected autoimmune disease, except for Type I diabetes mellitus,
hypothyroidism requiring only hormone replacement, or skin disorders (such as
vitiligo, psoriasis, or alopecia) not requiring systemic therapy.
8. Active uncontrolled bacterial, viral, or fungal infection requiring systemic therapy.
9. Known history of testing positive for HIV, known AIDS.
10. Hepatitis B surface antigen positive or hepatitis C antibody positive. Further
investigation per institutional practices may be performed to exclude active
infection.
11. Patients with a condition requiring chronic systemic treatment with either
corticosteroids (>10 mg daily prednisone or equivalents) or other immunosuppressive
medications within 14 days before administration of Study Treatment. Inhaled or
topical steroids, or adrenal replacement dose of corticosteroids at dose ≤ 10 mg/day
prednisone equivalent are permitted.
12. Use of another investigational agent (drug or vaccine not marketed for any indication)
28 days or before administration of Study Treatment. If the investigational agent is a
monoclonal antibody then within 3 months before administration of Study Treatment
13. Pregnant or breast-feeding women.
14. Second malignancy unless in remission for 2 years or locally curable cancers that have
been treated with curative intent with no evidence of recurrence, such as:
- Basal or squamous cell skin cancer
- Superficial bladder cancer
- Carcinoma in situ of cervix or breast
- Incidental prostate cancer
- Non melanomatous skin cancer
- Carcinoma in situ of the cervix treated with curative intent
- Prostate cancer treated with curative intent with serum prostate specific antigen
(PSA) < 2.0 ng/mL
15. Patients with medical conditions requiring administration of strong cytochrome P450
(CYP), CYP3A4 Inducers and Inhibitors.
16. Uncontrolled adrenal insufficiency or active chronic liver disease.
17. Has received approved live vaccine/live attenuated vaccines within 30 days of planned
Cycle 1 Day 1. Inactivated viral vaccines or vaccines based upon subviral component
are allowed; however intranasal influenza vaccines (e.g. Flu-Mist) are not allowed.
COVID-19 vaccination should be administered at least 7 days before Cycle 1 Day 1.
18. Underlying medical conditions that, in the Investigator's opinion, will make the
administration of Study Treatment hazardous or obscure the interpretation of toxicity
determination or AEs.
19. Unwilling or unable to comply with procedures required in this protocol.