This is a Phase I clinical study of IMCgp100 in patients with advanced melanoma. In the Phase
I FIH study of IMCgp100 in advanced melanoma, a dose escalation was conducted with IMCgp100
administered on a weekly basis (Middleton, 2015). In this study, the MTD when IMCgp100 is
administered on a weekly basis was declared at 600 ng/kg. With a data cut off of 18 August
2015, it was observed that DLT of grade 3 (n=3) and grade 4 (n=1) hypotension in the weekly
dosing cohort was observed with the first dose in this trial. Based on observed safety and
the PK profile, a flat dosing regimen was implemented across the program and the RP2D of the
RP2D-QW was identified as 50 mcg QW.
In this same FIH study, several patients with metastatic uveal melanoma were treated in the
weekly dosing regimen at the MTD dose level (600 ng/kg) and as well at the dose level above
MTD, 900 ng/kg (n=5, data cut off 18 August 2015). Based on review of the observed objective
responses in the Phase I trial in UM as well as objective responses noted in cutaneous
melanoma, it was noted that patients with larger diameters of disease burden (both cutaneous
and UM) experienced objective tumor responses at the higher overall exposures to IMCgp100.
The intra-patient dose escalation study design is based on 2 observations in the clinic: (1)
objective partial and minor tumor responses in patients with higher tumor burdens were
generally observed at the higher absolute doses in the Phase I trial and (2) the occurrences
of more severe toxicity leading to dose limitation were limited to the first 2 weeks of
dosing on C1D1 and C1D8. Based on these 2 observations, it is hypothesized that an increased
exposure to drug in the weeks following the occurrence of the more severe toxicity (at the
first 2 doses) may lead to an enhanced tumor response in a setting of an unfavorable tumor
microenvironment such as UM.
This is a Phase I study of IMCgp100 administered on a weekly basis with an intra-patient
escalation dosing regimen. The intra-patient escalation occurs at the third weekly dose on
Cycle 1 Day 15 (C1D15). According to this regimen, all patients in the trial will receive 2
weekly doses of IMCgp100 at a dose level below the identified weekly recommended Phase II
dose (RP2D-QW) and then a dose escalation will commence at the third weekly dose at C1D15
with the goal to achieve a long-term dosing regimen at a dose higher than that identified for
the straight weekly dosing regimen (RP2D-QW). The dose escalation will identify the RP2D-IE.
The Phase I portion of the study will be a standard 3+3 dose escalation design. After the
dose escalation portion is complete and the recommended Phase II dose of the intra-patient
escalation dose regimen (RP2D-IE) is identified, an expansion cohort in metastatic uveal
melanoma will be completed. This cohort will enroll patients with metastatic uveal melanoma
with any prior therapy and will number up to approximately 40 patients.
Inclusion Criteria:
1. Male or female patients age ≥ 18 years of age at the time of informed consent
2. Ability to provide and understand written informed consent prior to any study
procedures
3. Histologically or cytologically confirmed diagnosis of metastatic uveal melanoma (mUM)
4. Surgically sterile patients or patients of child-bearing potential who agree to use
highly effective methods of contraception during study dosing and for 6 months after
last dose of study drug
5. Life expectancy of >3 months as estimated by the investigator
6. Human leukocyte antigen (HLA)-A2 positive
7. ECOG Performance Status of 0 or 1 at Screening
8. Patients must have disease (measurable or non-measurable acceptable) according to
Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1 criteria
Exclusion Criteria:
1. Presence of symptomatic or untreated central nervous system (CNS) metastases, or CNS
metastases that require doses of corticosteroids within the prior 3 weeks to Study Day
1. Asymptomatic and adequately treated CNS metastases are not exclusionary
2. History of severe hypersensitivity reactions to other biologic drugs or monoclonal
antibodies
3. Patient with any out-of-range laboratory values defined as:
- Serum creatinine > 1.5 x upper limit of normal (ULN) and/or creatinine clearance
(calculated using Cockcroft-Gault formula, or measured) < 50 mL/min
- Total bilirubin > 1.5 x ULN, except for patients with Gilbert's syndrome who are
excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN
- ALT > 3 x ULN
- AST > 3 x ULN
- Absolute neutrophil count < 1.0 x 10^9/L
- Absolute lymphocyte count < 0.5 x 10^9/L
- Platelet count < 75 x 10^9/L
- Hemoglobin < 8 g/dL
- Potassium, magnesium, corrected calcium or phosphate abnormality of National
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) >
grade 1
4. Clinically significant cardiac disease or impaired cardiac function, including any of
the following:
- Clinically significant and/or uncontrolled heart disease such as congestive heart
failure (New York Heart Association grade ≥2), uncontrolled hypertension or
clinically significant arrhythmia currently requiring medical treatment
- QTcF >470 msec on screening ECG or congenital long QT syndrome
- Acute myocardial infarction or unstable angina pectoris < 6 months prior to
Screening
5. Active infection requiring systemic antibiotic therapy. Patients requiring systemic
antibiotics for infection must have completed therapy before Screening
6. Known history of HIV infection. Testing for HIV status is not necessary unless
clinically indicated
7. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection per institutional
protocol. Testing for HBV or HCV status is not necessary unless clinically indicated
or the patient has a history of HBV or HCV infection
8. Patients receiving systemic treatment with systemic steroid therapy or any other
immunosuppressive medication at any dose level that would interfere with the action of
the study drugs in the opinion of the investigator
9. Malignant disease, other than that being treated in this study. Exceptions to this
exclusion include the following: malignancies that were treated curatively and have
not recurred within 2 years prior to study treatment; completely resected basal cell
and squamous cell skin cancers; any malignancy considered to be indolent and that has
never required therapy; and completely resected carcinoma in situ of any type
10. Any medical condition that would, in the investigator's judgment, prevent the
patient's participation in the clinical study due to safety concerns, compliance with
clinical study procedures or interpretation of study results
11. Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. For
cytotoxic or immunotherapy agents that can present with major delayed toxicity (eg,
anti-CTLA-4), 4 weeks is indicated as washout period
12. Presence of NCI CTCAE ≥ grade 2 toxicity (except alopecia, peripheral neuropathy and
ototoxicity, which are excluded if ≥ NCI CTCAE grade 3) due to prior cancer therapy
13. Chronic systemic corticosteroid use (ie, prednisone > 10 mg QD or the equivalent);
treatment for well-controlled and asymptomatic adrenal insufficiency is permitted, but
replacement dosing is limited to prednisone ≤ 10 mg QD or the equivalent, and patients
must have no history of adrenal crisis. Local steroid therapies (eg, otic, ophthalmic,
intra-articular or inhaled medications) are acceptable
14. Major surgery within 2 weeks of the first dose of study drug (minimally invasive
procedures such as bronchoscopy, tumor biopsy, insertion of a central venous access
device, and insertion of a feeding tube are not considered major surgery and are not
exclusionary)
15. Radiotherapy within 2 weeks of the first dose of study drug, with the exception of
palliative radiotherapy to a limited field, such as for the treatment of bone pain or
a focally painful tumor mass
16. Use of hematopoietic colony-stimulating growth factors (eg, G-CSF, GMCSF, M-CSF) ≤ 2
weeks prior to start of study drug. Patients must have completed therapy at least 2
weeks before the screening period begins with any hematopoietic colony-stimulating
growth factors. An erythroid stimulating agent is allowed as long as it was initiated
at least 2 weeks prior to the first dose of study treatment and the patient is not red
blood cell transfusion dependent
17. Pregnant, likely to become pregnant, or lactating women (where pregnancy is defined as
the state of a female after conception and until the termination of gestation)
18. Patients with adrenal insufficiency or patients currently requiring chronic, systemic
corticosteroid therapy at any dose for longer than 2 weeks. Local steroid therapies
(eg, otic, ophthalmic, intraarticular, or inhaled medications) are acceptable
