This is a Phase 1 open label, dose-escalation study evaluating the safety, pharmacokinetics,
pharmacodynamics, immunogenicity, and efficacy of the Fc-engineered variant 2141-V11 in
patients with previously treated relapsed or refractory solid tumors and locally advanced or
metastatic solid tumors to the skin amenable to intratumoral injection.
There are two parts to the study: a dose-finding stage (Part I), and a dose expansion stage
(Part II). Both Part I and Part II of the study will include patients with locally advanced
or metastatic cancers of the skin which are not amenable to standard treatment.
A traditional 3 + 3 dose escalation design will be used (Part I). Successive cohorts of
participants (3 participants/cohort) will be started on a fixed dose intratumoral injection
of 2141V11 at the dose assigned to their cohort. The study drug, 2141-V11, will be dosed once
every 3 weeks. The study drug is administered in cycles.
The first group of study participants in Part I will receive the lowest dose of study drug.
The next group of study participants will receive the next higher dose. This dosing scheme
continues until the maximum tolerated dose is determined. The maximum tolerated dose (MTD)
will be defined as 1 dose level below the dose in which DLTs are observed in >33% of the
participants.
Participants in Part II of the study will receive the MTD determined from Part 1 (dose
escalation) of the study. Part II participants in the study will also receive two
vaccinations (KLH and tetanus) to allow monitoring of their immune function.
Participants in both Part I and II can continue to receive cycles of study drug at their
assigned dose if they do not experience progression of disease, a serious adverse event, and
the study is ongoing.
Inclusion Criteria:
1. Age > 18 years old
2. Must have measurable or evaluable metastatic disease (at least more than 1 lesion) as
evidenced by physical exam or imaging
3. Must have an identifiable metastatic lesion of the skin, subcutaneous tissue, or lymph
node amenable to intratumoral injection. This includes all solid tumors as well as
metastatic melanoma and/or melanoma with in-transit metastases.
4. ECOG performance status < 1
5. Histologically confirmed diagnosis of refractory or relapsed metastatic disease
6. Required values for screening laboratory tests:
- Absolute neutrophil count (ANC) > 1000/mm3 independent of growth factor support
- Platelets > 75,000/mm3
- Hemoglobin > 8 g/dl
- Creatinine clearance > 40 ml/min for the dose-escalation phase, >25 ml/min in
dose expansion phase (if safety data from dose escalation indicate this is
possible)
- AST/ALT < 3 x ULN
- Bilirubin < 1.5 x ULN (except for participants with Gilbert's Syndrome or of
non-hepatic origin)
7. Patients must have refractory or relapsed disease and have must have exhausted all
standard-of-care therapy for their disease
8. Must be at least 4 weeks since treatment with checkpoint inhibitors or other
antibody-based therapy or investigational agents
9. Must be at least 2 weeks since chemotherapy, targeted small molecule therapy, cytokine
therapy, or radiation therapy, and be recovered from any clinically significant
toxicity experienced during treatment.
10. If sexually active male or female, and participating in sexual activity that could
lead to pregnancy, agrees to use two effective methods of contraception (i.e. condom
with spermicide, diaphragm with spermicide, hormone-eluting IUD, hormone-based
contraceptive with condom). For females, these restrictions apply for 1 month after
the last dose of study drug. For males, these restrictions apply for 3 months after
the last dose of study drug. Men must agree not to donate sperm during and after the
study.
Female study participants of reproductive potential are defined as pre-menopausal
women who have not had a sterilization procedure (e.g. hysterectomy, bilateral
oophorectomy, tubal ligation or salpingectomy). Women are considered menopausal if
they have not had a menses for at least 12 months and have a FSH of greater than 40
IU/L or if FSH testing is not available, they have had amenorrhea for 24 consecutive
months.
11. Women of childbearing potential must have a negative (beta-human chorionic
gonadotropin [b-hCG] pregnancy test at screening, as well as a negative pregnancy test
prior to each treatment
12. Life expectancy greater than 16 weeks (should be evaluated by a prognostic score,
e.g., Roya Marsden score).
13. Able to comply with the treatment schedule as determined by the participant and the
LIP
Exclusion Criteria:
1. Concurrent anticancer therapy including investigational agents. This includes topical
therapeutic agents.
2. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced
pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic
organizing pneumonia), risk of pulmonary toxicity, or evidence of active pneumonitis
on screening chest CT scan.
3. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
4. Patients with active hepatitis B (defined as having a positive hepatitis B surface
antigen (HBsAg) test at screening.
5. Patients with past/resolved hepatitis B virus (HBV) infection (defined as having a
negative HBsAg and a positive antibody to hepatitis B core antigen antibody test) are
eligible only if polymerase chain reaction is negative for HBV RNA. HBV DNA must be
obtained in these patients prior to Cycle 1, Day 1.
6. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
7. Has spinal cord compression not definitively treated with surgery and/or radiation or
previously diagnosed and treated spinal cord compression without evidence that disease
has been clinically stable for > 2 weeks prior to screening.
8. Vaccinated with live, attenuated viral vaccines within 4 weeks of enrollment.
9. Known history of human immunodeficiency virus (HIV) or any uncontrolled active
systemic infection.
10. Major surgery or a wound that has not fully healed within 4 weeks of enrollment.
11. Treatment with an immunosuppressive regimen of corticosteroids or other
immunosuppressive medication (e.g., methotrexate, rapamycin) within 30 days of study
treatment. Note: patients with adrenal insufficiency may take up to 5 mg of prednisone
or equivalent daily. Topical and inhaled corticosteroids in standard doses are
allowed.
12. Severe infections within 4 weeks prior to Cycle 1, Day 1, including, but not limited
to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
13. Signs and symptoms of infection within 2 weeks prior to Cycle 1, Day 1.
14. Any investigational therapy within 28 days prior to initiation of study treatment.
This includes topical or injected agents.
15. Significant cardiovascular disease (i.e., NYHA class 3 congestive heart failure;
myocardial infarction within the past 6 months; unstable angina; coronary angioplasty
within the past 6 months; uncontrolled atrial or ventricular cardiac arrhythmias.
16. Autoimmune disease including systemic lupus erythematosus, rheumatoid arthritis,
multiple sclerosis, Sjogren's syndrome, autoimmune thrombocytopenia, history of
uveitis or other autoimmune disease if clinically significant.
17. Patients with clinically active brain metastases are excluded. Patients with stable
brain metastasis (with or without intervention) are eligible. Patients with previously
irradiated lesions are eligible provided patient is >4 weeks beyond completion of
cranial irradiation and >3 weeks of corticosteroid therapy.
18. Known history of leptomenigeal disease, patients with metastases to the brain stem,
midbrain, pons, or medulla, and patients with metastases with 10 mm of the optic
apparatus (optic nerve and chiasm) will be excluded from the study.
19. Requires anticoagulation with warfarin or equivalent vitamin K antagonists.
20. Has had a pulmonary embolism or any other thromboembolic event within 6 months prior
to study entry.
21. Prior toxicities from previous cancer therapy, including checkpoint inhibition, that
have not regressed to Grade < 1 severity (NCI CTCAE v4.03, or later versions) within
28 days before Cycle 1, Day 1, with the exception of alopecia.
22. Active hepatitis C are excluded. Patients positive for hepatitis C virus (HCV)
antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
23. Any surgical procedure within less than 14 days of the first receipt of study drug.
Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of the
need for a major surgical procedure during the study other than for diagnosis.
24. Pregnant or breast feeding
25. Active infection or with a fever >38.5o C within 3 days prior to the first scheduled
treatment.
26. Any medical history, including laboratory results, deemed by the investigator to be
likely to interfere with their participation in the study, or to interfere with the
interpretation of the results, or any social condition that, in the opinion of the
Investigator, might pose additional risk to the participant or confound the results of
the study.
