| Eligibility |
Inclusion Criteria:
1. Be willing and able to give written informed consent for the study.
2. Be = 18 years of age on day of informed consent.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
4. Histologically or cytologically confirmed diagnosis of cutaneous or mucosal melanoma.
5. Known BRAF status.
6. Have unresectable stage III or stage IV melanoma. Patients must have progressed on
treatment with an anti-PD-1/L1 monoclonal antibody (mAb) administered as monotherapy,
or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment
progression is defined by meeting all of the following criteria:
1. Received at least 6 weeks of standard dosing of an approved anti-PD-1/L1 mAb.
2. Demonstrated disease progression (PD) on or after PD-1/L1 as defined by RECIST
v1.1. The initial evidence of PD is to be confirmed by a second assessment no
less than four weeks from the date of the first documented PD, in the absence of
rapid clinical progression.
3. Progressive disease documented within 12 weeks from the last dose of anti-PD-1/L1
mAb.
i. This determination is made by the investigator. Once PD is confirmed, the initial
date of PD documentation will be considered the date of disease progression.
7. Anti-PD-1-based therapy should have been the last line of systemic therapy as part of
first line treatment. Prior treatment either in neo or adjuvant setting is allowed (if
patient did not develop progressive disease while on receiving it). In the case of
patients who develop progressive disease during adjuvant therapy, that treatment will
be counted as one prior line, and will be eligible if only that prior line has been
administered.
8. At least one tumoral lesion that is RECIST 1.1 measurable and amenable for IT
injection.
9. At least one accessible tumor lesion that is amenable to weekly injection. If liver is
a site of injection, presence of at least one additional tumor lesion outside the
liver amenable for injection.
10. Willingness to provide biological samples required for the duration of the study
including a fresh tumor biopsy sample. NOTE: If possible, the biopsied lesion should
be a non-target lesion.
11. Adequate hematologic and organ function defined by the following laboratory results
obtained within 2 weeks prior to the first dose of study treatment:
1. Absolute neutrophil count (ANC) = 1.5 x 10^9/L
2. Platelet count = 100 x 10^9/L
3. Hemoglobin (Hgb) = 9 g/dL
4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 2.5x upper
limit of normal (ULN) (5 × ULN if presence of liver metastases)
5. Serum total bilirubin =1.5 ×ULN OR direct bilirubin =ULN for participants with
total bilirubin levels >1.5 × ULN
6. Prothrombin time (PT) (or international normalized ratio [INR]) within normal
limits and activated partial prothrombin time (aPTT) within normal limits
7. Serum creatinine = 1.5 × ULN or creatinine clearance = 30 mL/min (calculated per
institutional standard)
12. Female patient of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the injection of study medication. If the
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will
be required.
13. Female patients who are not pregnant or breastfeeding or expecting to conceive or
father children within the projected duration of the study, starting with the
screening visit through 120 days after the last dose of study treatment.
Female patients of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile or abstain from heterosexual activity from the
beginning of the study through 120 days after receiving the last dose of study
medication. Patients of childbearing potential are those who have not been surgically
sterilized or have not been free from menses for > 1 year.
Non-pregnant, non-breast-feeding women may be enrolled if they are willing to use 2
methods of birth control or are considered highly unlikely to conceive. Highly
unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a
woman who is =45 years of age and has not had menses for greater than 1 year will be
considered postmenopausal), or 3) not heterosexually active for the duration of the
study. The two birth control methods can be either: two barrier methods or a barrier
method plus a hormonal method to prevent pregnancy.
14. Patients should be informed that taking the study medication may involve unknown risks
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to
participate in the study, they must adhere to the contraception requirement (described
above). If there is any question that a patient will not reliably comply with the
requirements for contraception, that patient should not be entered into the study.
15. Male patients should agree to use an adequate method of contraception from the
beginning of the study through 120 days after receiving the study medication.
16. In countries where human immunodeficiency virus (HIV) positive patients can be
included, HIV infected participants must be on anti-retroviral therapy (ART) and have
a well-controlled HIV infection/disease defined as:
1. Participants on ART must have a CD4+ T-cell count >350 cells/mm3 at time of
screening;
2. Participants on ART must have achieved and maintained virologic suppression
defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of
qualification (below the limit of detection) using the locally available assay at
the time of screening and for at least 12 weeks prior to screening;
3. Participants on ART must have been on a stable regimen, without changes in drugs
or dose modification, for at least 4 weeks prior to study entry (Day 1).
17. Able and willing to comply with study and follow-up procedures.
Exclusion Criteria
1. Uveal melanoma.
2. Prior grade 3-4 irAE due to immune checkpoint inhibitors requiring systemic steroids
for more than 2 weeks.
3. Prior intra-tumoral treatments.
4. If a liver lesion is the site of injection:
1. macroscopic tumor infiltration by the lesion to be injected into the main portal
vein, hepatic vein or vena cava;
2. portal vein thrombosis;
3. prior embolization of liver lesions;
4. radiofrequency, cryotherapy or microwave ablation in the last 6 months;
5. Child-Pugh B or C;
6. All AST, ALT and bilirubin greater than >2.5 ULN.
5. Contraindications to tumor biopsy and injections of the metastasis(es), such as
coagulopathy, therapeutic dose anticoagulant treatment and treatment with long-acting
agents such as clopidogrel which cannot be safely stopped.
6. Chemotherapy or biological cancer therapy within 4 weeks prior to the first dose of
study treatment. Note: Participants must have recovered from all adverse events (AEs)
due to previous therapies to = Grade 1 or baseline. Participants with = Grade 2
neuropathy may be eligible.
7. Palliative radiotherapy within 1 week of start of study treatment. Subjects must have
recovered from all radiation-related toxicities, not require corticosteroids, and not
have had radiation pneumonitis.
8. Clinically active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are radiologically stable, i.e., without evidence of progression for at least 4
weeks by repeat imaging (note that the repeat imaging should be performed during study
screening), clinically stable and without requirement of steroid treatment for at
least 14 days prior to first dose of study treatment.
9. History of a second malignancy, unless potentially curative treatment has been
completed with no evidence of malignancy for 2 years.
10. Allergy to BO-112 and/or any of its excipients.
11. Allergy to pembrolizumab and/or any of its excipients.
12. Active infection requiring systemic therapy.
13. History of (non-infectious) pneumonitis/interstitial lung disease that required
steroids or current pneumonitis/interstitial lung disease.
14. Active autoimmune disease that 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) is not considered a form
of systemic treatment and is allowed.
15. Receiving systemic immunosuppressive therapy within 28 days before enrolment with the
exceptions of intranasal, topical, and inhaled corticosteroids or oral corticosteroids
at physiological doses not exceeding 10 mg/day of prednisone or equivalent.
16. HIV-infected participants with a history of Kaposi sarcoma and/or Multicentric
Castleman Disease.
17. Known history of hepatitis B (defined as HbsAg reactive) or known active hepatitis C
(defined as HCV RNA [qualitative] detected) virus infection. Patients who are
hepatitis B surface antigen negative and HBV viral DNA negative are eligible.
1. Patients who had HBV but have received an antiviral treatment and show
non-detectable viral DNA for 6 months are eligible.
2. Patients who are seropositive because of HBV vaccine are eligible.
3. Patients who had HCV but have received an antiviral treatment and show no
detectable HCV viral DNA for 6 months are eligible.
18. Has received a live vaccine within 28 days prior to the first dose of study drug. For
COVID vaccines a 72 hour wash out period is necessary.
19. History of allogenic tissue or solid organ transplant.
20. Is currently participating or has participated in a study of an investigational agent
or has used an investigational device within 4 weeks prior to the first dose of study
treatment (patients who are in a follow-up phase of an investigational study may
participate as long as it has been 4 weeks after the last dose of the previous
investigational agent).
21. Any clinically significant psychiatric, social, or medical condition that, in the
opinion of the Investigator, could increase patient's risk, interfere with protocol
adherence, or affect a patient's ability to give informed consent.
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