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LUMINOS-103: A basket trial evaluating the safety and efficacy of PVSRIPO and PVSRIPO in combination with Anti-PD-1/L1 checkpoint inhibitors in patients with advanced solid tumors

Description

This is a phase 1/2, open-label, multi-center, single arm basket study evaluating the administration of PVSRIPO ± anti programmed cell death protein 1 (PD 1)/programmed death-ligand 1 (PD L1) monoclonal antibody (mAb) therapy (which will be referred to throughout this protocol as "anti-PD-1/L1 therapy") in adult patients with solid tumor cancers. Bladder Cancer and Head and Neck Squamous Cell Carcinoma have been selected as the first tumor specific cancers of interest for enrollment.

Status

Accepting new patients

Primary Study Objective(s)

The primary objective of this trial is to determine:

  • Safety and Tolerability: Number of participants with treatment-related adverse events as assessed by CTCAE
  • Tumor Response measured by RECIST 1.1

Core eligibility

Note: This is only a partial list of eligibility criteria.

Master protocol inclusion criteria:

  • Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
  • Age ≥ 18 years of age at the time of signing the informed consent.
  • Prior CDC-recommended vaccination series against PV and has received a boost immunization with trivalent Poliovirus Vaccine Inactivated (IPOL®) (Sanofi-Pasteur SA) at least 1 week, but less than 6 weeks, prior to Cycle 1 Day 1.

* Note: Patients who are unsure of their vaccination status must provide evidence of anti-PV immunity prior to enrollment, as applicable.

  • Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
  • A formalin-fixed paraffin-embedded (FFPE) tumor specimen (from archival or fresh biopsy) with an associated pathology report documenting the histology of the tumor type of interest must be confirmed to be available to send to the Sponsor.

* Note: additional details can be found in the tumor specific appendix.

  • Eastern Cooperative Oncology Group (ECOG) status of 0 or 1.
  • Adequate bone marrow and liver function as assessed by the following:
    • Hemoglobin ≥9.0 g/dl (patients may be transfused)
    • Lymphocyte count ≥ 0.5 x 109/L (500/µL)
    • Absolute neutrophil count (ANC) ≥1.5 x 109/L (1500/µL)
    • Platelet count ≥100 x 109/L (100,000/µL) without transfusion
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN)
      • Subjects with documented liver metastases: AST and ALT ≤5 x ULN
    • Serum total bilirubin ≤1.5 x ULN OR direct bilirubin <ULN for patients with total bilirubin > 1.5 x ULN
    • For patients not receiving therapeutic anticoagulation: international normalized ratio (INR), prothrombin time (PT), partial thromboplastin time (PTT) (or activated partial thromboplastin time [aPTT]) ≤ 1.5 x ULN
  • Resolution of nonhematologic toxicities from prior therapy or surgical procedures to ≤ Grade 1 or baseline (except alopecia).
  • Contraceptive use by men or women of childbearing potential should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
  • Any radiotherapy, chemotherapy, immunotherapy, biological, investigational, or hormonal therapy for cancer treatment (except for adjuvant hormonal therapy for breast cancer or prostate cancer defined as M0 disease or prostate-specific antigen persistence/recurrence without metastatic disease) within 21 days of Cycle 1 Day 1.
  • Patients requiring anticoagulation with warfarin are excluded. Additional eligibility criteria for anticoagulation requirements for each solid tumor cancer of interest will be provided in the tumor specific appendix.
  • Presence of central nervous system (CNS) metastases requiring immediate treatment with radiation therapy or steroids (ie, patient must be off steroids administered for brain metastases for ≥ 14 days prior to Cycle Day 1). Leptomeningeal disease is excluded regardless of clinical stability or treatment status.
  • Clinically significant (ie, active) cardiovascular disease at the time of signing the informed consent; for example, cerebrovascular accidents (≤ 6 months before the first dose of PVSRIPO), myocardial infarction (≤ 6 months before the first dose of PVSRIPO), unstable angina, serious cardiac arrythmia requiring medication, or uncontrolled symptomatic congestive heart failure [Class II or higher as defined by the New York Heart Association [NYHA] functional classification system; see Appendix 4]).
  • QTcF interval > 450 msec (males) or > 470 msec (females) at Screening (confirmed in triplicate). For patients with ventricular pacemakers or bundle branch block, QTcF >500 msec.
  • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Cycle Day 1, or anticipation of the need for major surgical procedure during the course of the study.
  • Active or history of autoimmune disease or immune deficiency within previous 2 years, with the following exceptions:
    • History of autoimmune-related hypothyroidism that is managed by thyroid replacement hormone
    • Type 1 diabetes mellitus that is well-controlled (as determined by the Investigator) by an established insulin regimen
    • Eczema, psoriasis, or lichen simplex chronicus with dermatologic manifestations only (eg, patients with psoriatic arthritis are excluded), provided all of the following conditions are met:
      • Rash must cover < 10% of body surface area
      • Disease is well-controlled (as determined by the Investigator) at baseline and requires only low-potency topical corticosteroids
      • No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within 12 months of Cycle 1 Day 1
  • History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug-induced or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan.
    • History of radiation pneumonitis in the radiation field (fibrosis) is allowed.
  • Uncontrolled pleural effusion, pericardial effusion, or ascites; patients with indwelling catheters (eg, PleurX®) are allowed.
  • Known serious active infection (eg, human immunodeficiency virus [HIV], hepatitis B or C, tuberculosis, etc.).
    • Participants with a negative hepatitis B surface antigen (HBsAg) test and a positive total hepatitis B core antibody (HBcAb) test are allowed.
    • History of positive hepatitis C virus (HCV) antibody test, but negative HCV RNA test is allowed.
    • Participants with a historical positive HIV test are not allowed.
  • Treatment with systemic immunosuppressive medication within 28 days of Cycle 1 Day 1, with the following exceptions:
    • Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (eg, 48 hours of corticosteroids for a contrast allergy) are eligible.
    • Patients receiving mineralocorticoids (eg, fludrocortisone), or systemic prednisone equivalent corticosteroid doses of < 10 mg per day are eligible for the study.
  • Prior allogeneic or autologous hematopoietic stem cell or bone marrow transplantation.
  • Receipt of any live, attenuated vaccines within 28 days of Cycle 1 Day 1. Vaccination to prevent symptomatic SARS-CoV-2 infection is allowed as long as the vaccine is NOT a live attenuated vaccine (e.g. adenovirus-based constructs); however, the vaccine should be administered ≥ 1 week before or after a PVSRIPO injection.
  • Known hypersensitivity to any of the drugs used in this study.
  • Pregnant or lactating women.
  • History of human serum albumin allergy.
  • History of neurological complications due to PV infection.
  • History of agammaglobulinemia.
  • Legal incapacity or limited legal capacity.
  • Other uncontrolled serious chronic disease or psychiatric condition that in the Investigator's opinion could affect the patient's safety, compliance, or follow-up in the protocol.

Bladder Cancer Specific Inclusion Criteria:

Both Cohorts:

  • Histologically or cytologically confirmed urothelial carcinoma arising from the lower urinary tract and amenable to intratumoral injection. Both urothelial carcinoma and mixed urothelial/non-urothelial cell histologies are allowed. Patients with pure non-urothelial histologies are excluded.
  • Measured or calculated (per institutional standard) creatinine clearance ≥ 45 ml/min (GFR can also be used in place of creatinine clearance).
  • A formalin-fixed paraffin-embedded (FFPE) tumor specimen (from archival or fresh biopsy if collection date of archival specimen > 6 months prior to Cycle 1 Day 1) with an associated pathology report documenting the histology of the tumor type of interest must be confirmed to be available to send to the Sponsor.

Cohort A:

  • Clinical stage T2-T4a, N0-1, M0 by computed tomography (CT) abdomen/pelvis urogram or magnetic resonance imaging (MRI) abdomen/pelvis urogram.
  • Have refused or are ineligible for cisplatin-based therapy, defined as meeting one of the following criteria. Note: the master protocol excludes patients with Eastern Cooperative Oncology Group (ECOG) ≥ 2 or congestive heart failure New York Heart Association (NYHA) class ≥ II.
    • Glomerular filtration rate (GFR) < 60 mL/min calculated per institutional standard
    • Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 Grade ≥ 2 hearing loss
    • CTCAE v 5.0 Grade ≥ 2 peripheral neuropathy NOTE: the hearing loss and peripheral neuropathy criteria are exceptions to the criterion in the master protocol stating all nonhematologic toxicities from prior therapy or surgical procedures be ≤ Grade 1 or baseline.
  • Fit and planned for cystectomy (according to local guidelines).
  • Have received no prior systemic therapy for MIBC.
  • Must have post-TURBT site/lesion amenable for injection via cystoscopy (determined by the Investigator).
  • Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 is NOT required. This is an exception to the inclusion criterion outlined in the master protocol.

Cohort B:

  • Unresectable locally advanced or metastatic bladder cancer
    • T4b, any N
    • Any T, N 2-3
    • Any T, any N, M1
  • Have received no more than one prior line of systemic therapy in the unresectable/metastatic setting; systemic therapy given in the neoadjuvant or adjuvant setting, where the last date of administration is ≤ 12 months prior to the date of recurrence will be considered a line of therapy in the unresectable/metastatic setting.
  • Must have lesion that is amenable to injection via cystoscopy of intact bladder (per the Investigator) and at least one measured dimension ≥ 1 cm.
  • Must have at least 1 lesion amenable to biopsy a. The lesion must be safely accessible as determined by the investigator and should not be located at sites that require significant risk procedures to biopsy. Examples of sites considered to be of significant risk include but are not limited to: biopsies of the brain, lung, mediastinum, pancreas, or endoscopic procedures extending beyond the esophagus, stomach, or bowel wall.

Bladder Cancer Specific Exclusion Criteria:

Both Cohorts:

  • Warfarin is prohibited. Anticoagulant and antiplatelet medications will be managed by the treating physician, per local institutional guidelines, to optimize the safety of intratumoral injection of PVSRIPO.
  • Received prior treatment with a PD-1/L1 inhibitor for any malignancy including early-stage bladder cancer.
  • Received prior treatment with an agent directed to another stimulatory or co-inhibitory T-cell receptor.

Cohort A:

1. TURBT does not qualify as a major surgery/procedure or open biopsy (see exclusion criterion in master protocol).

Head and Neck Cancer Specific Inclusion Criteria:

Both Cohorts

  • Must have an injectable lesion measuring ≥ 1.0 cm in at least one diameter that is visible, palpable, or detectable by ultrasound. Lesions located in sites considered to be of more significant risk for complications from PVSRIPO injection and associated inflammation are not to be injected. Examples include:
    • Lesions located in the liver, lung, pancreas, bowel, and other visceral organs are not considered injectable.
    • Lesions encasing or immediately adjacent to major blood vessels including the carotid artery are not considered injectable.
    • Lesions that have been treated with curative levels of radiation and have not healed from radiation-associated toxicities are not considered injectable.
  • Documentation of p16-positive or p16-negative disease by CLIA/CAP-approved test to determine HPV status of tumor for HNSCC of the oropharynx.
    • Note: If local results are not available, then a sample (tissue on microscopic slides, tissue block or a fresh tissue biopsy in formalin) should be sent to the central laboratory for analysis.
    • Note: Oral cavity, hypopharynx, and larynx cancer are not required to undergo HPV testing by p16 testing as by convention these tumor locations are assumed to be HPV negative.
  • A formalin-fixed paraffin-embedded (FFPE) tumor specimen (from archival or new biopsy if collection date of archival specimen > 6 months prior to Cycle 1 Day 1) with an associated pathology report documenting the histology of the tumor type of interest must be confirmed to be available to send to the Sponsor.
    • Must have a minimum of 15 unstained, freshly cut, serial sections from an FFPE tumor specimen (or FFPE block equivalent) available.
    • If fewer than 15 slides are available at baseline, the patient may still be eligible upon discussion with the Medical Monitor.
  • Must have at least 1 lesion amenable to biopsy
    • The lesion must be safely accessible as determined by the investigator and should not be located at sites that require significant risk procedures to biopsy. Examples of sites considered to be of significant risk include but are not limited to: biopsies of the brain, lung, mediastinum, pancreas, or endoscopic procedures extending beyond the esophagus, stomach, or bowel wall.
  • HIV positive patients are eligible to enroll provided the following criteria have been met:
    • CD4+ T cell counts ≥ 350μl/μL
    • No history of AIDS-defining opportunistic infections within the last 12 months
    • Have been on established antiretroviral therapy (ART) for at least four weeks and have an HIV RNA viral load of < 400 copies/mL prior to the first dose of study drug NOTE: this criterion is an exception to Exclusion Criterion #10 in the master protocol (Section 4.2) stating patients with an active HIV infection are excluded from enrollment
  • Patients with a history of chronic HCV are eligible to enroll provided the following criteria have been met:
    • Have completed curative antiviral treatment OR been on established antiviral therapy for HCV for at least 4 weeks prior to the first dose of study drug.
    • Have an HCV RNA viral load below the limit of quantification. NOTE: this criterion is an exception to Exclusion Criterion #10 in the master protocol (Section 4.2) stating patients with an active HCV infection are excluded from enrollment.
  • Patients with a history of HBV infection are eligible to enroll provided the following criteria have been met:
    • On HBV prophylaxis for at least 1 week prior to first dose of study drug
    • Have an HBV DNA viral load below the lower limit of quantification. NOTE: this criterion is an exception to Exclusion Criterion #10 in the master protocol (Section 4.2) stating patients with an active HBV infection are excluded from enrollment.

Cohort C

  • Histologically- or cytologically-confirmed SCC of the oral cavity, oropharynx, hypopharynx, or larynx
  • Histologically confirmed carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary, and salivary gland or non-squamous histologies (eg mucosal melanoma) are not allowed
  • Clinical stage II-IVA disease where the primary and neck metastases are considered resectable, and the intent of treatment is curative.
    • Oral cavity, p16 negative oropharynx, hypopharynx, larynx: T2-T3, N0; T1-T3, N1-N2; T4a, N0-N2
    • p16 positive oropharynx: T0-T2, N2-N3; T3, N0-N3; T4, N0-N3
  • No prior therapy (eg surgery, chemotherapy, radiation etc.) for the study cancer. Note: if the study cancer is considered to be a second (or third etc) primary, any treatment received to treat the first primary cancer is not exclusionary as long as the first primary is considered to be "cured", i.e no evidence of disease related to the first primary.
    • Systemic/intratumoral therapy ≤ 6 months prior to the first dose of study drug is exclusionary.
  • Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 is NOT required. Note: This is an exception to Inclusion Criterion #4 (Section 4.2) in the master protocol, which requires measurable disease.

Cohort D

  • Histologically- or cytologically-confirmed recurrent or metastatic (R/M) SCC of the oral cavity, oropharynx, hypopharynx, or larynx that is not amenable to local therapy with curative intent (ie surgery or radiation therapy with or without chemotherapy)
  • Histologically confirmed recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary, and salivary gland or non-squamous histologies (eg mucosal melanoma) are not allowed
  • No prior systemic/intratumoral therapy in the R/M setting.
    • Systemic/intratumoral therapy for locally advanced disease which was completed ≤ 6 months prior to the first dose of study drug is exclusionary.
  • Tumor expression of PD-L1 with CPS ≥1 using the PD-L1 IHC 22C3 pharmDx test.

Head and Neck Cancer Specific Exclusion Criteria:

Both Cohorts

  • Patients requiring oxygen supplementation.
  • Patients whose anticoagulation or antiplatelet medications cannot be managed by local institutional guidelines to accommodate the safe intratumoral injection of PVSRIPO, as determined by the treating