IRB Study Number 21-686
Status Recruiting
Phase Phase 1
Institute Taussig Cancer Institute
Description
Primary Objectives
For Part A: To determine the safety and tolerability of mRNA4157 monotherapy in subjects with resected solid tumors.
For Parts B, C and D: To determine the safety, tolerability, and RP2D of mRNA4157 administered in combination with pembrolizumab.
Secondary Objectives
For Part A apheresis expansion cohort – To assess the immunogenicity of mRNA-4157 in subjects with resected solid tumors.
For Part B biopsy expansion cohort – To assess modulation of relevant biomarkers in tumors by mRNA-4157 in combination with pembrolizumab.
For Part C HNSCC: To characterize preliminary antitumor activity of mRNA4157 in combination with pembrolizumab.
For Part D – To assess the immunogenicity of mRNA-4157 and pembrolizumab from apheresis samples in subjects with resected cutaneous melanoma.
Exploratory Objectives
To assess the immunogenicity of mRNA-4157 with or without pembrolizumab from blood samples.
To characterize the antitumor activity of mRNA4157 with or without pembrolizumab.
To evaluate changes in relevant blood borne biomarkers (which may include but are not limited to circulating tumor DNA [ctDNA] and circulating cytokines) and potential correlation to clinical outcome.
To explore the relationship between NGS data obtained from the mandatory fresh tumor biopsy required at study entry versus NGS data obtained retrospectively from available archival tumor
biopsies.
- To assess any impact of mRNA-4157 on pembrolizumab exposure.
Inclusion Criteria
Male or female, ≥ 18 years old with the ability to understand and provide signed and witnessed informed consent and agree to comply with protocol requirements.
Subjects must be clinically disease-free at study entry (i.e., subjects in the adjuvant setting). Subjects will be permitted to complete any standard of care adjuvant therapy, and those not eligible for any standard of care adjuvant treatment, or who decline such treatment, are permitted to consent to this study, as long as all treatment options have been transparently disclosed and documented in the Subject’s medical record.
Subjects must have one of the histologically- or cytologically-confirmed unresectable (locally advanced or metastatic) solid malignancies listed in criterion 4, AND have measurable disease at study entry defined by RECIST 1.1 (tumor lesions situated in a previously irradiated area are considered measurable if progression has been measured in such lesions). AND be considered suitable for treatment with pembrolizumab; in this study pembrolizumab will be considered an investigational study drug and treatment can be administered either:
a. to subjects with cancers approved in the current pembrolizumab label i.e., “on-label”, or
b. to subjects for whom no standard therapies exist, or who are not eligible for or decline standard therapies, as long as all treatment options have been transparently disclosed and documented in the subject’s medical record. Note: PD-L1 testing for eligibility is not required.
- Subjects with any of the following solid malignancies:
a. Non-small cell lung cancer. Subjects in Part B must either lack EGFR sensitizing mutation or ALK translocation per local test results, or must have progressed on approved standard of care treatment for EGFR or ALK+ NSCLC.
b. Small cell lung cancer
c. Cutaneous melanoma
d. Bladder urothelial carcinoma
e. Human papillomavirus (HPV)-negative HNSCC
f. Any solid malignancy known to be MSI high/MMR deficient per local test results, including but not limited to: CRC, stomach adenocarcinoma (gastric cancer), esophageal adenocarcinoma and endometrial cancer.
g. Any solid malignancy known to have a high tumor mutational load/burden, as determined by prior sequencing report from a CLIA certified laboratory. For the purpose of this study, high mutation load/burden is defined as:
• ≥100 total mutations (non-synonymous somatic single nucleotide variants), as determined by WES, or
• Test result of “High” TMB or TML, as determined by targeted sequencing platforms (eg, Caris or FoundationOne®).
- Subjects must have one of the histologically or cytologically confirmed unresectable (locally advanced or metastatic) solid malignancies listed below, AND must be naïve to anti-PD-1/PD-L1 therapy, AND must have measurable disease at study entry defined by RECIST 1.1 (tumor lesions situated in a previously irradiated area are considered measurable if progression has been measured in such lesions).
a. MSS-CRC:
• MSS status will be based on local CLIA-certified IHC or PCR assay.
• Disease must have progressed after treatment with approved standard therapies, including fluoropyrimidine-, oxaliplatin- and irinotecancontaining chemotherapy, and, if KRAS wild type, an anti-EGFR therapy.
b. HPV negative metastatic or recurrent HPV negative HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx:
• For first line treatment: Patients with metastatic or unresectable, recurrent HPV negative HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test. PD-L1 status documentation should be provided to Sponsor prior to enrolling the patient.
• Ineligible for platinum containing chemotherapy or
• Disease must have progressed after treatment with a platinum-containing regimen, and should be defined as one of the following:
− Disease progression or recurrence between 3 to 6 months of prior curatively intended multimodal therapy (which includes platinum therapy) for locoregionally advanced HPV negative HNSCC.
− Disease progression or recurrence after prior platinum therapy in the recurrent or metastatic setting. Note: This criterion is only applicable for subjects who have not had treatment in the recurrent/metastatic setting.
c. Bladder urothelial carcinoma:
• Disease must have progressed after treatment with a platinum-containing chemotherapy, or
• Ineligible for first-line platinum-containing chemotherapy.
Subjects with completely resected Stage II, III or IV cutaneous melanoma.
For Part A and D, subjects must have an FFPE tumor sample available (e.g., from their prior surgery) that is suitable for the NGS required for this study.
For Parts B and C, subjects must have at least 1 lesion amenable to the fresh tumor biopsy at study entry and provide a biopsy suitable for the NGS required for this study. An existing (archival) FFPE tumor sample may instead be used for NGS, but only if the subject has not received any cancer treatment believed capable of potentially modifying the neoantigen profile of the disease since the time that the existing FFPE tumor sample was taken (each case must be discussed with the Sponsor to determine suitability).
All tumor samples will undergo NGS at study entry, therefore the tumor sample for each subject must:
a. Meet the minimum standards for tissue quantity and quality as defined in the Laboratory Manual for this study, and
b. Pass the required QC checks for NGS by the Sponsor’s NGS vendor.
Subjects must have resolution of toxic effect(s) from prior therapy to Grade 1 or less. Subjects with ≤ Grade 2 neuropathy or alopecia are an exception to this criterion. If a subject received major surgery or radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or complications to Grade 1 or less.
Female subjects cannot be pregnant or lactating/breastfeeding: Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of trial medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female subjects of childbearing potential must be willing to use an adequate method of contraception (detailed in Section 4.1.3.2) for the duration of the study until 120 days after the last dose of either mRNA-4157 or pembrolizumab. Note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
Male subjects of childbearing potential must agree to use an adequate method of contraception (detailed in Section 4.1.3.2) for the duration of the study until 120 days after the last dose of either mRNA-4157 or pembrolizumab. Note: abstinence is acceptable if this is the usual lifestyle and preferred contraception of the subject.
Subjects with PS of 0 or 1 on the ECOG Performance Scale.
In the opinion of the Investigator, life expectancy > 12 weeks at Screening.
Subjects with normal organ and marrow function reported at screening:
a. Absolute neutrophil count (ANC) > 1,500/μL
b. Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L
c. Platelets ≥ 100,000/ μL (without growth factor support)
d. PT or INR and aPTT ≤ 1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
e. Total bilirubin ≤ 1.5 × ULN OR direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 × ULN
f. AST and ALT ≤ 2.5 × ULN. (Subjects with documented liver metastases may have AST and ALT ≤ 5 × ULN)
g. Creatinine ≤ 1.5 × institutional ULN or measured or calculateda creatinine clearance ≥ 60 mL/min for subject with creatinine > 1.5 × institutional ULN. Glomerular filtration rate can also be used in place of creatinine or creatinine clearance. Creatinine clearance should be calculated per institutional standard
- Subjects participating in the Part A Apheresis Expansion Phase Cohort, and Part D must provide mandatory consent to the required apheresis procedures, and must have palpable veins suitable for apheresis, as determined by the clinician performing the apheresis procedure. Subjects must also satisfy any additional inclusion criteria per the local institutional apheresis procedure.
Exclusion Criteria
- Treatment with any of the following:
a. Any investigational agents or study drugs from a previous clinical study within 4 weeks of the first dose of mRNA-4157 or pembrolizumab (note only a 2 week wash out is required from prior pembrolizumab treatment).
b. Any anti-cancer monoclonal antibody within 4 weeks of the first dose of mRNA-4157 or pembrolizumab (note only a 2 week wash out is required from prior pembrolizumab treatment).
c. Any chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks of the first dose of mRNA-4157 or pembrolizumab.
d. Live-virus vaccination within 30 days of the first dose of mRNA-4157 or pembrolizumab. Seasonal flu vaccines that do not contain live virus are permitted.
e. Any anti-cancer therapeutic vaccine within 4 weeks of the first dose of mRNA-4157 or pembrolizumab.
f. Any immunostimulant (e.g., IL-2) within 4 weeks of the first dose of mRNA-4157 or pembrolizumab.
g. Any systemic steroid therapy or other form of immunosuppressive therapy within 7 days of the first dose of mRNA-4157 or pembrolizumab. A physiologic dose of systemic corticosteroids may be approved after consultation with the Sponsor. Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
h. Transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including G-CSF, GM-CSF or recombinant erythropoietin) within 1 week of the screening blood sample (including the NGS blood sample), and within 4 weeks of the first dose of mRNA-4157 and/or pembrolizumab. Blood transfusions are allowed at any other time during the study. Note: prior PD-1/PD-L1 treatment is permitted for subjects in Parts A, B and D of this study after discussion and agreement with the Sponsor, and only if the subject did not discontinue due to drug-related toxicity. Patients with a best overall response of progressive disease will not be allowed on the study.
Active central nervous system metastases and/or carcinomatous meningitis. Note: Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging (using the identical imaging modality for each assessment, either CT scan or MRI) for at least 4 weeks prior to the first dose of mRNA-4157 or pembrolizumab and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
Active autoimmune disease that has 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.
Has a history of (noninfectious) pneumonitis that required steroids or current pneumonitis.
Has a diagnosis of immunodeficiency.
Any clinically significant cardiac disease defined as New York Heart Association class III or IV within the past 6 months of Screening, unless, in the opinion of the Investigator, the disease is well-controlled.
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, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
Previously identified hypersensitivity to components of the formulations used in this study.
Had a solid organ or allogeneic bone marrow transplant.
Subjects with a history of interstitial lung disease.
An active infection requiring systemic therapy.
A known history of HIV (HIV 1/2 antibodies).
Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone curative therapy or in situ cervical cancer.
Subjects participating in apheresis; mandatory in the Part A apheresis expansion phase cohort and Part D (optional for other study parts), must not meet any of the exclusion criteria on any day when apheresis is performed, either presented below, or per local institutional apheresis protocol.
a. Prior history of difficulty obtaining peripheral blood through phlebotomy
b. Weight <120 lbs
c. High blood pressure > 160/100
d. Low blood pressure < 100/70
e. Known blood coagulation disorder
f. Platelets < 50,000/mm3
g. PTT > 2x ULN
h. INR > 1.3
i. Use of aspirin, NSAIDs, Plavix®, Coumadin, or other blood thinners that cannot be stopped for clinical reasons for 5 days before and 5 days after each apheresis procedure
j. Albumin < 2.0 g/dL
