MC# 16-39 - Phase 1 Open Label, Multicenter Study of MK-1454 Administered by Intratumoral Injection as Monotherapy and in Combination with Pembrolizumab for Patients with Advanced/Metastatic Solid Tumors or Lymphomas

  • Agent(s): MK-1454, Pembrolizumab
  • Disease Type(s): Bladder, Breast, Cervical, Colorectal, Endometrial, Esophageal, Gastric, Head and Neck, Hepatocellular, Lung-NSCLC, Lung-SCLC, Lymphoma, Melanoma, Mesothelioma, Neuroendocrine, Ovarian, Pancreatic, Prostate, Renal, Sarcoma, Solid Tumor, Squamous Cell, Thyroid, Cholangiocarcinoma
  • Phase(s): I
  • Drug Classification(s): Targeted Therapy, Immunotherapy, Small Molecule
  • Molecular Target(s): PD-1, PD-L1 (CD274)

Mechanism of Action

MK-1454 is a Stimulator of Interferon Genes (STING) agonist that activates the STING pathway, which involves induction of type-I interferons and other pro-inflammatory cytokines that potentiate T-cell activation

Purpose

In this study, the sponsor and investigators want to learn:

  • How much MK-1454 and Pembrolizumab can be given with an acceptable level of side effects
  • The effects of MK-1454 in combination with Pembrolizumab
  • How much MK-1454 is absorbed into the blood and how fast it is removed
  • If research tests can be used in the future to predict who will benefit from MK-1454
Inclusion Criteria
  • Be ≥ 18 years of age on day of signing informed consent.

  • Voluntarily agreed to participate by giving written informed consent. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.

  • Have a histologically- or cytologically-confirmed advanced/metastatic solid tumor or lymphoma by pathology report for which there is no standard available therapy. Solid tumors and lymphomas of any type are eligible for enrollment. Tumor types of greatest interest include, but are not limited to, malignant melanoma, head and neck squamous cell carcinoma, breast adenocarcinoma, and lymphomas.

  • Have stage III or stage IV disease that is not surgically resectable. Stage IIB CTCL subjects are eligible.

  • Have at least one injectable lesion which is amenable to injection and biopsy. Biopsy may be performed via visual inspection, ultrasound guidance, or cross-sectional imaging. Intratumoral injection for cutaneous lesions may be performed via visual inspection. Intratumoral injection for subcutaneous lesions may be performed via ultrasound guidance or via palpation.. This injectable lesion must be measurable

    • A cutaneous or subcutaneous lesion ≥ 1 cm in longest diameter for solid tumors, or ≥ 1.5 cm in short axis for a nodal lesion in solid tumor subjects. The longest diameter for an injectable lesion must be ≤ 10 cm for both solid tumors and nodal lesions in solid tumor subjects.

    • Multiple coalescing, superficial lesions which in aggregate have a longest diameter of ≥ 1 cm and ≤ 10 cm.

    • For lymphoma, a nodal lesion ≥ 1.5 cm in short axis, or an extra-nodal lesion ≥ 1 cm in 2 dimensions. The longest diameter for an injectable lesion must be ≤ 10 cm.

  • Have at least 1 discrete and/or distant non-injected lesion which is amenable to biopsy via visual inspection or amenable to biopsy via image guidance. This lesion must be measurable as defined by the response criteria used to assess the subject (RECIST 1.1 for solid tumors or revised IWG criteria for lymphomas).

    • For RECIST 1.1, ≥ 1 cm in longest diameter for non-nodal lesions, or ≥ 1.5 cm in the short axis for nodal lesions.

    • For revised IWG, a nodal lesion ≥ 1.5 cm in longest diameter or ≥ 1.0 cm in short axis, or an extra-nodal lesion ≥ 1 cm in two dimensions.

  • Have an ECOG Performance Status of 0 or 1.

  • Demonstrate adequate organ function as defined by the following table (Table 1). All screening labs should be performed within 7 days prior to treatment initiation.

Table 1 Adequate Organ Function Laboratory Values

System

Laboratory Value

Hematological

Absolute neutrophil count

>1,500/mcL(>1,000/mcL for lymphoma subjects)

Platelets

>100,000/mcL

subjects)

(>75,000/mcL

for

lymphoma

Hemoglobin

>9 g/dL or > 5.6 mmol/L (>8 g/dL or > 5.0 mmol/L for lymphoma subjects)

Renal

Serum Creatinine or

Creatinine Clearance (CrCl) (measured or calculated)a or

Glomerular Filtration Rate (GFR) in place of CrCl

< 1.5 X ULN or

> 60 mL/min for subject with creatinine levels > 1.5 X ULN

Hepatic

Total bilirubin ( serum)

< 1.5 X ULN or

Direct bilirubin < ULN for subjects with total bilirubin levels > 1.5 X ULN

Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT)

< 2.5 X ULN

Coagulation

International Normalized Ratio (INR) or Prothrombin Time (PT)

Activated Partial Thromboplastin Time (aPTT)

< 1.5 X ULN

 

< 1.5 X ULN

a Creatinine clearance should be calculated per institutional standard

*Criteria must be met without packed red blood cell (pRBC) transfusion within the prior 2 weeks. Subjects can be on stable dose of erythropoietin (> approximately 3 months)

 

  • Female subjects of childbearing potential must have a negative urine or serum pregnancy test at Screening and again within 72 hours prior to receiving the first dose of study treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the subject to be eligible.

  • Female subjects of childbearing potential must be willing to use highly effective methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 180 days after last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free of menses for > 1 year. Male subjects of reproductive potential must agree to use an acceptable method of contraception during sexual contact with females of childbearing potential starting with the first dose of study medication through 180 days after the last dose of study therapy.

  • HIV-infected participants must meet these additional criteria:

    • Have HIV-1 infection documented by an licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry (Day 1) and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 p24 antigen, or plasma HIV-1 RNA VL.

    • Have well-controlled HIV on anti-retroviral therapy (ART), defined as:

  1. Must have a CD4+ T-cell count >350 cells/mm3 at time of screening

  2. Must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of quantification) using the locally available assay at the time of screening and for at least 12 weeks prior to screening

  3. 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)

Exclusion Criteria
  • Has had chemotherapy,  definitive radiation, or biological cancer therapy within 4 weeks (2 weeks for palliative radiation) prior to the first dose of study therapy, or has not recovered to baseline or CTCAE grade 1 (Grade 2 alopecia is allowed) from the adverse events due to cancer therapeutics administered more than 4 weeks earlier.
  • Is currently participating and receiving study therapy or has participated in a study of an investigational agent and has received study therapy or has used an investigational device within 28 days of administration of MK-1454.
    • Note: Prior exposure to immunotherapeutics is allowed, including PD-1 and PD-L1 inhibitors, provided patient did not experience a ≥ Grade 3 drug related toxicity on monotherapy with a PD-1 or PD-L1 inhibitor
  • Is expected to require any other form of antineoplastic therapy while on study.
  • Is on chronic systemic steroid therapy in excess of replacement doses (prednisone ≤ 10 mg/day is acceptable), or on any other form of immunosuppressive medication.
    • Note: The use of physiologic replacement doses of corticosteroids may be approved after consultation with the Sponsor Medical Monitor or designee.
  • Has a history of a second malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for 5 years.
    • Note: The time requirement does not apply to subjects who underwent successful definitive     resection of basal cell carcinoma of the skin, superficial bladder cancer or in situ cervical cancer.
  • Has clinically active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain or meningeal metastases may participate and be eligible for treatment provided they are stable and asymptomatic (without evidence of progression by MRI scan of the brain separated by at least 4 weeks after treatment), have no evidence of new or enlarging brain metastases, are evaluated within 4 weeks prior to first study drug administration, and are off immunosuppressive doses of systemic steroids at least 2 weeks from enrollment.
  • Has had a severe hypersensitivity reaction to treatment with a monoclonal antibody.
  • Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs) except vitiligo or resolved childhood asthma/atopy. Replacement therapy, such as thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, is not considered a form of systemic treatment.
  • Has a history of vasculitis.
  • Has an active infection requiring therapy.
  • Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
  • Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years.
    • Note: Subjects who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of graft-versus-host disease (GVHD).
  • Has Hepatitis B or C infections, or is known to be positive for HBsAg/HBV DNA or Hepatitis C Antibody or ribonucleic acid (RNA). Active Hepatitis C virus (HCV) is defined by a known positive Hep C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay.
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, would make administration of the study drugs hazardous or make it difficult to monitor adverse effects such that it is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
  • Has known psychiatric or substance abuse disorders that would interfere in cooperation with the requirements of the trial.
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.
  • Has not fully recovered from any effects of major surgery, and be free of significant detectable infection. Surgeries that required general anesthesia must be completed at least 2 weeks before first study drug administration. Surgery requiring regional/epidural anesthesia must be completed at least 72 hours before first study drug administration and subjects should be recovered.
  • Has received a live vaccine within 30 days prior to first dose.
  • Has a history of re-irradiation for SCCHN at the projected injection site.
  • Has a tumor(s) in direct contact or encases a major blood vessel, and has ulceration and/or fungation onto the skin surface at the projected injection site.
  • HIV infected participants with history of Kaposi’s sarcoma and/or multicentric Castleman’s disease
  • HIV infected participants who have had an HIV-related opportunistic infection within 6 months
  • Drug-drug interactions have to be taken into consideration and decisions whether a particular drug can be used as a concomitant medication in the study should be based on recommendations at the time of the study and depending on the MOA of the study drug. Patients on ART agents with a potentially significant overlapping toxicity profile should be excluded if the therapy cannot be switched to the regimen without overlapping toxicity.

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT03010176?term=MK-1454&rank=1

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Re: MC# 16-39