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) (which will be referred to throughout this
protocol as "anti-PD-1/L1 therapy") 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.
Master Protocol Inclusion Criteria:
1. 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.
2. Age ≥ 18 years of age at the time of signing the informed consent.
3. 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.
4. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
5. 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.
6. Eastern Cooperative Oncology Group (ECOG) status of 0 or 1.
7. 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
8. Resolution of nonhematologic toxicities from prior therapy or surgical procedures to
≤ Grade 1 or baseline (except alopecia).
9. 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.
Master Protocol Exclusion Criteria:
1. 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.
2. 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.
3. 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.
4. 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]).
5. 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.
6. 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.
7. 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
8. 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.
9. Uncontrolled pleural effusion, pericardial effusion, or ascites; patients with
indwelling catheters (eg, PleurX®) are allowed.
10. 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.
11. 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.
12. Prior allogeneic or autologous hematopoietic stem cell or bone marrow transplantation.
13. 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.
14. Known hypersensitivity to any of the drugs used in this study.
15. Pregnant or lactating women.
16. History of human serum albumin allergy.
17. History of neurological complications due to PV infection.
18. History of agammaglobulinemia.
19. Legal incapacity or limited legal capacity.
20. 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:
1. 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.
2. Measured or calculated (per institutional standard) creatinine clearance ≥ 45 ml/min
(GFR can also be used in place of creatinine clearance).
3. 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:
1. Clinical stage T2-T4a, N0-1, M0 by computed tomography (CT) abdomen/pelvis urogram or
magnetic resonance imaging (MRI) abdomen/pelvis urogram.
2. 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.
1. Glomerular filtration rate (GFR) < 60 mL/min calculated per institutional
standard
2. Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 Grade ≥ 2 hearing
loss
3. 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.
3. Fit and planned for cystectomy (according to local guidelines).
4. Have received no prior systemic therapy for MIBC.
5. Must have post-TURBT site/lesion amenable for injection via cystoscopy (determined by
the Investigator).
6. 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:
1. Unresectable locally advanced or metastatic bladder cancer
1. T4b, any N
2. Any T, N 2-3
3. Any T, any N, M1
2. 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.
3. Must have lesion that is amenable to injection via cystoscopy of intact bladder (per
the Investigator) and at least one measured dimension ≥ 1 cm.
4. 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:
1. 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.
2. Received prior treatment with a PD-1/L1 inhibitor for any malignancy including
early-stage bladder cancer.
3. 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
1. 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:
1. Lesions located in the liver, lung, pancreas, bowel, and other visceral organs
are not considered injectable.
2. Lesions encasing or immediately adjacent to major blood vessels including the
carotid artery are not considered injectable.
3. Lesions that have been treated with curative levels of radiation and have not
healed from radiation-associated toxicities are not considered injectable.
2. Documentation of p16-positive or p16-negative disease by CLIA/CAP-approved test to
determine HPV status of tumor for HNSCC of the oropharynx.
1. 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.
2. 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.
3. 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.
1. Must have a minimum of 15 unstained, freshly cut, serial sections from an FFPE
tumor specimen (or FFPE block equivalent) available.
2. If fewer than 15 slides are available at baseline, the patient may still be
eligible upon discussion with the Medical Monitor.
4. 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.
5. HIV positive patients are eligible to enroll provided the following criteria have been
met:
1. CD4+ T cell counts ≥ 350μl/μL
2. No history of AIDS-defining opportunistic infections within the last 12 months
3. 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
6. Patients with a history of chronic HCV are eligible to enroll provided the following
criteria have been met:
1. 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.
2. 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.
7. Patients with a history of HBV infection are eligible to enroll provided the following
criteria have been met:
1. On HBV prophylaxis for at least 1 week prior to first dose of study drug
2. 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
1. Histologically- or cytologically-confirmed SCC of the oral cavity, oropharynx,
hypopharynx, or larynx
a. 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
2. Clinical stage II-IVA disease where the primary and neck metastases are considered
resectable, and the intent of treatment is curative.
1. Oral cavity, p16 negative oropharynx, hypopharynx, larynx: T2-T3, N0; T1-T3,
N1-N2; T4a, N0-N2
2. p16 positive oropharynx: T0-T2, N2-N3; T3, N0-N3; T4, N0-N3
3. 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.
a. Systemic/intratumoral therapy ≤ 6 months prior to the first dose of study drug is
exclusionary.
4. 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
1. 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)
a. 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
2. No prior systemic/intratumoral therapy in the R/M setting.
a. Systemic/intratumoral therapy for locally advanced disease which was completed ≤ 6
months prior to the first dose of study drug is exclusionary.
3. 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
1. Patients requiring oxygen supplementation.
2. 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 physician.
