Recurrent Head and Neck Cancer
Conditions
Keywords
Fludarabine, Adenovirus, Head & neck squamous cell carcinoma
Brief summary
Primary Objective: The primary objective of the study is to evaluate the safety of repeat administration of a dose level of Ad/PNP plus fludarabine phosphate (F-araAMP) which demonstrated anti-tumor activity in patients with advanced head and neck cancer in a completed phase I study. Secondary Objective: The secondary objective is to evaluate the antitumor activity of repeat administration of Ad/PNP plus F-araAMP. FDA Office of Orphan Drugs Division is a source of funding for the overall project.
Detailed description
1. Mechanism of action. The study drug, Ad/PNP-F-araAMP (Fludarabine phosphate) consists of a nonreplicating adenoviral vector expressing the E. coli purine nucleoside phosphorylase (PNP) injected intratumorally followed by intravenous administration of F-araAMP. This combination generates 2-fluoroadenine (F-Ade) within the tumor resulting in focal chemotherapeutic activity. F-araAMP is an agent that is rapidly cleaved by plasma phosphatases to fludarabine, which is the primary circulating form of the drug and has activity against certain hematological malignancies, but not against solid tumors such as head and neck squamous cell carcinoma (HNSCC). Fludarabine (F-araA) is an adenosine analog and substrate for E. coli PNP, which cleaves the glycosidic bond of F-araA to generate F-Ade. The F-Ade metabolite has shown pronounced activity against human tumor xenografts in mice. Many refractory tumors are refractory precisely because they have a very low growth fraction, i.e., a relatively small percentage of tumor cells dividing at any particular point in time. In nonclinical studies, significant in vivo antitumor activity has been demonstrated by F-Ade generation from F-araAMP in tumors in which 2.5 to 10% of cells express the E. coli PNP gene. In addition, anti-tumor effect was seen in patients with advanced solid tumors (melanoma and head and neck cancer) in the higher dose cohorts during a Phase 1 study (see next section). 2. Tumor response with Ad/PNP-F-araAMP in Phase 1 Study. The safety and efficacy of Ad/PNP-F-araAMP has been evaluated in a Phase 1 study, PNP-001 (NCT01310179). Four escalating dose levels were evaluated in 10 subjects with head and neck cancer and 2 subjects with melanoma; clinical activity was observed at the highest dose levels following 3 intratumoral injections of Ad/PNP over 2 days and IV F-araAMP phosphate over 3 days. The overall response rate (CR+PR) was approximately 67% in the 2 highest dose cohorts, Cohorts 3 and 4. Results suggest a dose response effect. The duration of response in the injected tumor was limited, with 4 of 5 responding tumors having disease progression of the injected lesion prior to last follow-up on Day 56, suggesting that repeat administration should be evaluated. Ad/PNP + F-araAMP was well tolerated. No subject experienced a dose-limiting toxicity and none of the subjects discontinued study treatment. Overall, the activity and safety profile of Ad/PNP seen in the Phase 1 study supports further clinical evaluation of repeat administration of Ad/PNP (IT) and F-araAMP phosphate infusion for patients with HNSCC. 3. Purpose of the Study. Based upon the tumor response seen with a single administration of the two highest dose levels of Ad/PNP-F-araAMP in the Phase 1 study (NCT01310179), PNP plans to investigate the safety and assess anti-tumor activity of repeat cycles of injection of Ad/PNP + F-araAMP in patients with advanced head and neck cancer. Subjects in the study will have RECIST 1.1 measurable HNSCC which is amenable to local injection for which there is no effective curative or palliative treatment option. This study population was selected since results from this Phase 1/2 trial are intended to support the safety of repeat dosing in further clinical investigation. 4. Study Design. The trial is designed as a single-arm study to evaluate the safety of repeat cycles of Ad/PNP and F-araAMP in patients with recurrent HNSCC with tumor(s) accessible for injection. Ad/PNP will be injected intratumorally twice on Day 1 and once on Day 2 followed by infusion of F-araAMP daily on Days 3, 4, and 5. Subjects will receive repeat administration of Ad/PNP-F-araAMP every 4 weeks (i.e., each cycle) for 5 cycles or until injected tumor progresses, unacceptable toxicity occurs, no tumor is present for injection, or patient death. Tumor response in the injected tumor(s) will be assessed by physical examination as well as by radiographic imaging. All subjects will be monitored for adverse events during study participation.
Interventions
BIOLOGICALAd/PNP
Ad/PNP is a replication defective adenoviral vector expressing E. coli Purine Nucleoside Phosphorylase
DRUGFludarabine Phosphate
Fludarabine phosphate is an anticancer agent currently used for treatment of patients with chronic lymphocytic leukemia.
Sponsors
Stanford University
Emory University
Thomas Jefferson University
GeoVax, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provided Informed Consent 2. Age ≥ 18 years 3. Patients with histologically or cytologically confirmed diagnosis of recurrent cancer of the head and neck region for whom there is no curative treatment option. For the purposes of trial eligibility, cancers of the head and neck shall include, in addition to head and neck squamous cell carcinoma (HNSCC), cutaneous squamous cell primary sites and squamous cell carcinoma of unknown primary presenting with neck lymph nodal disease, as well as nasopharyngeal carcinoma, and salivary gland tumors. 4. All standard or approved treatment options that would provide substantive palliation must have failed, been exhausted, or patient not eligible or willing to use them (for example neuropathy, nephropathy , or hearing loss precluding the use of cisplatin) 5. Tumor mass (primary tumor and/or lymphadenopathy) measurable by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and technically suitable for intratumoral injections (otolaryngologist will determine feasibility). Patients with nodal disease (or metastatic disease) that is needle accessible are eligible. Patients with additional tumors (including distant metastatic disease) beyond the intratumoral injection accessible tumor(s) that are not accessible for intratumoral injection are eligible ONLY if the patient has no other treatment option for the metastatic disease and treatment of local disease may provide the patient some benefit or palliation. 6. Eastern Cooperative Oncology Group performance status of ≤ 2 7. In the judgment of the Investigator, the patient has recovered sufficiently from any previous significant therapy side effects or toxicities prior to Ad/PNP administration. 8. Absolute neutrophil count ≥ 1,500 cells/ul; hemoglobin ≥ 9 g/dl, platelets ≥ 100,000/ul 9. Serum creatinine ≤ 1.5 mg/dl, or calculated creatinine clearance ≥ 60 ml/min 10. Bilirubin ≤ upper limit of normal, alanine aminotransferase ≤ 1.5 x upper limit of normal and/or aspartate aminotransferase ≤ 1.5 x upper limit of normal, alkaline phosphatase ≤ 2.5 x upper limit of normal 11. Prothrombin time (PT)/international normalized ratio (INR) ≤ 1.5 x upper limit of normal 12. Activated partial thromboplastin (aPTT) time ≤ 1.5 x upper limit of normal 13. Female patients must have a negative urine or serum pregnancy at screening (pregnancy test is not required for patients with bilateral oophorectomy and/or hysterectomy or for those patients who are \> 1 year postmenopausal) 14. All patients of reproductive potential must agree to use a medically acceptable form of contraception (eg, hormonal birth control, double-barrier method) or abstinence.
Exclusion criteria
1. Prior history or current diagnosis of leukemia 2. Have received any gene therapy products or oncolytic viral therapy 3. Receiving allopurinol 4. Received an investigational drug within 30 days prior to first injection of Ad/PNP 5. Received radiation treatment \< 4 weeks prior to first injection of Ad/PNP, and does not have any RECIST 1.1 evaluable lesions that are outside the radiation field. (If the patient has RECIST 1.1 evaluable lesions outside the radiation field then they can be included.) 6. Received chemotherapy (systemic anticancer treatment) \< 4 weeks prior to first injection of Ad/PNP and has not recovered from all the related side effects. (If the patient has recovered from all related side effects or has reached a new baseline, then they may begin receiving treatment at sooner than 4 weeks) 7. Have significant baseline neuropathy (\> Grade 2 based on Common Terminology Criteria for Adverse events \[CTCAE\] v5.0) 8. Uncontrolled intercurrent disease (e.g., diabetes, hypertension, thyroid disease, active infection) 9. Had within 6 months prior to enrollment: Myocardial infarction, cerebral vascular accident, uncontrolled congestive heart failure, significant liver disease, unstable angina 10. Fever (temperature \> 38.1 degrees C orally) 11. Receiving chronic systemic corticosteroids (\> 3 weeks) or any chronic immunosuppressive medications within 14 days prior to first injection of Ad/PNP. Subjects receiving short courses of corticosteroids are considered eligible for the study. 12. Receiving anticoagulants other than those to maintain patency of venous lines 13. Women who are pregnant or breast feeding 14. History of HIV infection. No requirement for testing.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety Measures (Adverse Events and Laboratory Parameters) With Repeat Cycles of Treatment. | up to 7 months | Safety measures evaluated by medical history, physical examination, vital signs, inspection of tumor site, performance status, EKG, chest X-ray (CXR), blood chemistry, hematology, CD4/CD8 T-cell counts, urinalysis, PT/PTT, blood sample for adenovirus, urine for adenovirus, F-Ade plasma level, blood sample for antibody against adenovirus, and monitoring adverse events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response for Injected Tumors During 5 Cycles of Treatment as Determined by RECIST 1.1. | up to 7 months | Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. |
| Progression Free Survival (PFS) - Time From First Intratumoral Injection to Date of Progression or Death, Calculated in Months | up to 7 months | Time to Event (Progression or Death) was defined as time from first intratumoral injection to date of progression or death for any cause, whichever occurred first, and was calculated, in months, as: (Date of first PD (Progressive Disease) or death or censoring - date of first intratumoral injection + 1) / 30.4375. PD was defined, based on the protocol-defined criteria for response in For-Injection tumors, as at least a 20% increase in the longest diameter (LD) of the injected lesions, taking as reference the smallest LD recorded on study (this includes the baseline LD if that is the smallest on study; note: appearance of one or more new lesions was considered progression in assessing overall tumor response.). PFS derivation did not include tumor assessments collected after the end of study treatment as these were not planned for collection beyond the final cycle. |
| Probability of No Progressive Disease or Death and 95% CI Up to 6 Months (%) | 6 months | Time to PD or death was defined as time from the first intratumoral injection to date of progression or death for any cause, whichever occurs first, and was calculated, in months, as: (Date of first PD or death or censoring - date of first intratumoral injection + 1) / 30.4375. |
| Overall Survival (OS) - Time From First Intratumoral Injection to Date of Death up to 60 Days Post Last Injection | up to 7 months | Time to death was defined as time from the first intratumoral injection to date of death for any cause, and was calculated, in months, as: (Date of death or censoring - date of the first intratumoral injection + 1) / 30.4375. Subjects still alive as of the data cut-off date were censored on the last known alive date from mortality status follow up. For subjects that were lost to follow up, the last visit in the database or last contact date where the subject was documented to be alive was used to estimate last known date alive. |
| Probability of No Death and 95% CI up to 1 Month and up to 6 Months | 6 months | Time to death was defined as time from the first intratumoral injection to date of death for any cause, and was calculated, in months, as: Date of death or censoring - date of the first intratumoral injection + 1 / 30.4375. |
Countries
United States
Participant flow
Pre-assignment details
10 subjects provided consent; however, only 8 subjects were assigned to the treatment group as one subject died and one subject was determined ineligible (per protocol entry criteria) prior to treatment assignment.
Participants by arm
| Arm | Count |
|---|---|
| Ad/PNP + Fludarabine Phosphate, 5 Cycles Ad/PNP: Ad/PNP is a replication defective adenoviral vector expressing E. coli Purine Nucleoside Phosphorylase
Fludarabine Phosphate: Fludarabine phosphate is an anticancer agent currently used for treatment of patients with chronic lymphocytic leukemia. | 8 |
| Ad/PNP + Fludarabine Phosphate, 5 Cycles Ad/PNP: Ad/PNP is a replication defective adenoviral vector expressing E. coli Purine Nucleoside Phosphorylase
Fludarabine Phosphate: Fludarabine phosphate is an anticancer agent currently used for treatment of patients with chronic lymphocytic leukemia. | 20 |
| Total | 28 |
Baseline characteristics
| Characteristic | Ad/PNP + Fludarabine Phosphate, 5 Cycles |
|---|---|
| Age, Continuous | 58.8 years STANDARD_DEVIATION 8.01 |
| Disease Characteristics at Baseline - ECOG Grade 0 | 1 Participants |
| Disease Characteristics at Baseline - ECOG Grade 1 | 5 Participants |
| Disease Characteristics at Baseline - ECOG Grade 2 | 2 Participants |
| Disease Characteristics at Baseline - Summary of Diameters of For-Injection Lesions | 50.30 mm STANDARD_DEVIATION 36.542 |
| Disease Characteristics at Baseline - Summary of Diameters of Target Lesions | 92.93 mm STANDARD_DEVIATION 76.255 |
| Disease History - Duration of Time from Initial Diagnosis (months) | 44.90 months STANDARD_DEVIATION 18.184 |
| Disease History - Histological Type Other | 2 Participants |
| Disease History - Histological Type Squamous cell carcinoma | 6 Participants |
| Disease History - Progression/Recurrence/Metastasis Location Hypopharynx | 1 Participants |
| Disease History - Progression/Recurrence/Metastasis Location Larynx | 1 Participants |
| Disease History - Progression/Recurrence/Metastasis Location Lymph node | 4 Participants |
| Disease History - Progression/Recurrence/Metastasis Location Nasal cavity | 1 Participants |
| Disease History - Progression/Recurrence/Metastasis Location Other | 4 Participants |
| Disease History - Progression/Recurrence/Metastasis Location Pharynx | 2 Participants |
| Disease History - Progression/Recurrence/Metastasis Location Soft tissue | 1 Participants |
| Disease History - Progression/Recurrence/Metastasis Specification Metastasis | 5 Participants |
| Disease History - Progression/Recurrence/Metastasis Specification Progression - Local | 1 Participants |
| Disease History - Progression/Recurrence/Metastasis Specification Progression - Regional | 3 Participants |
| Disease History - Progression/Recurrence/Metastasis Specification Recurrence - Local | 4 Participants |
| Disease History - Progression/Recurrence/Metastasis Specification Recurrence - Regional | 2 Participants |
| Disease History - Progression/Recurrence/Metastasis Specification Regional | 1 Participants |
| Disease History - Staging at First Diagnosis II | 1 Participants |
| Disease History - Staging at First Diagnosis III | 3 Participants |
| Disease History - Staging at First Diagnosis IV | 3 Participants |
| Disease History - Staging at First Diagnosis Missing | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 8 | 1 / 2 |
| other Total, other adverse events | 8 / 8 | 0 / 0 |
| serious Total, serious adverse events | 5 / 8 | 0 / 0 |
Outcome results
Primary
Safety Measures (Adverse Events and Laboratory Parameters) With Repeat Cycles of Treatment.
Safety measures evaluated by medical history, physical examination, vital signs, inspection of tumor site, performance status, EKG, chest X-ray (CXR), blood chemistry, hematology, CD4/CD8 T-cell counts, urinalysis, PT/PTT, blood sample for adenovirus, urine for adenovirus, F-Ade plasma level, blood sample for antibody against adenovirus, and monitoring adverse events.
Time frame: up to 7 months
Population: Defined as all participants who received any intratumoral administrations of Ad/PNP or any infusion of F-araAMP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ad/PNP + Fludarabine Phosphate, 5 Cycles | Safety Measures (Adverse Events and Laboratory Parameters) With Repeat Cycles of Treatment. | Any Serious TEAE | 5 Participants |
| Ad/PNP + Fludarabine Phosphate, 5 Cycles | Safety Measures (Adverse Events and Laboratory Parameters) With Repeat Cycles of Treatment. | Dose Limiting Toxicity TEAE | 0 Participants |
| Ad/PNP + Fludarabine Phosphate, 5 Cycles | Safety Measures (Adverse Events and Laboratory Parameters) With Repeat Cycles of Treatment. | Serious Adverse Events | 5 Participants |
| Ad/PNP + Fludarabine Phosphate, 5 Cycles | Safety Measures (Adverse Events and Laboratory Parameters) With Repeat Cycles of Treatment. | Fatal SAEs | 0 Participants |
| Ad/PNP + Fludarabine Phosphate, 5 Cycles | Safety Measures (Adverse Events and Laboratory Parameters) With Repeat Cycles of Treatment. | Any TEAE | 8 Participants |
| Ad/PNP + Fludarabine Phosphate, 5 Cycles | Safety Measures (Adverse Events and Laboratory Parameters) With Repeat Cycles of Treatment. | Any TEAE Related to Study Treatment | 8 Participants |
| Ad/PNP + Fludarabine Phosphate, 5 Cycles | Safety Measures (Adverse Events and Laboratory Parameters) With Repeat Cycles of Treatment. | Any TEAE Related to Non-Study Treatment | 1 Participants |
| Ad/PNP + Fludarabine Phosphate, 5 Cycles | Safety Measures (Adverse Events and Laboratory Parameters) With Repeat Cycles of Treatment. | Any TEAE Grade 3 or Greater | 7 Participants |
| Ad/PNP + Fludarabine Phosphate, 5 Cycles | Safety Measures (Adverse Events and Laboratory Parameters) With Repeat Cycles of Treatment. | Any TEAE Leading to Study Discontinuation | 1 Participants |
| Ad/PNP + Fludarabine Phosphate, 5 Cycles | Safety Measures (Adverse Events and Laboratory Parameters) With Repeat Cycles of Treatment. | Any TEAE Grade 3 or Greater Related to Study Treatment | 3 Participants |
Secondary
Best Overall Response for Injected Tumors During 5 Cycles of Treatment as Determined by RECIST 1.1.
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time frame: up to 7 months
Population: All participants who received at least three intratumoral administrations of Ad/PNP and any infusion of F-araAMP.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ad/PNP + Fludarabine Phosphate, 5 Cycles | Best Overall Response for Injected Tumors During 5 Cycles of Treatment as Determined by RECIST 1.1. | Stable Disease | 3 Participants |
| Ad/PNP + Fludarabine Phosphate, 5 Cycles | Best Overall Response for Injected Tumors During 5 Cycles of Treatment as Determined by RECIST 1.1. | Progressive Disease | 2 Participants |
| Ad/PNP + Fludarabine Phosphate, 5 Cycles | Best Overall Response for Injected Tumors During 5 Cycles of Treatment as Determined by RECIST 1.1. | Not Evaluable | 3 Participants |
Secondary
Overall Survival (OS) - Time From First Intratumoral Injection to Date of Death up to 60 Days Post Last Injection
Time to death was defined as time from the first intratumoral injection to date of death for any cause, and was calculated, in months, as: (Date of death or censoring - date of the first intratumoral injection + 1) / 30.4375. Subjects still alive as of the data cut-off date were censored on the last known alive date from mortality status follow up. For subjects that were lost to follow up, the last visit in the database or last contact date where the subject was documented to be alive was used to estimate last known date alive.
Time frame: up to 7 months
Population: All participants who received at least three intratumoral administrations of Ad/PNP and any infusion of F-araAMP.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ad/PNP + Fludarabine Phosphate, 5 Cycles | Overall Survival (OS) - Time From First Intratumoral Injection to Date of Death up to 60 Days Post Last Injection | 7.0 Months |
Secondary
Probability of No Death and 95% CI up to 1 Month and up to 6 Months
Time to death was defined as time from the first intratumoral injection to date of death for any cause, and was calculated, in months, as: Date of death or censoring - date of the first intratumoral injection + 1 / 30.4375.
Time frame: 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ad/PNP + Fludarabine Phosphate, 5 Cycles | Probability of No Death and 95% CI up to 1 Month and up to 6 Months | Up to 1 month | 87.5 percentage of subjects |
| Ad/PNP + Fludarabine Phosphate, 5 Cycles | Probability of No Death and 95% CI up to 1 Month and up to 6 Months | Up to 6 months | 72.9 percentage of subjects |
Secondary
Probability of No Progressive Disease or Death and 95% CI Up to 6 Months (%)
Time to PD or death was defined as time from the first intratumoral injection to date of progression or death for any cause, whichever occurs first, and was calculated, in months, as: (Date of first PD or death or censoring - date of first intratumoral injection + 1) / 30.4375.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ad/PNP + Fludarabine Phosphate, 5 Cycles | Probability of No Progressive Disease or Death and 95% CI Up to 6 Months (%) | 56.3 percentage of subjects |
Secondary
Progression Free Survival (PFS) - Time From First Intratumoral Injection to Date of Progression or Death, Calculated in Months
Time to Event (Progression or Death) was defined as time from first intratumoral injection to date of progression or death for any cause, whichever occurred first, and was calculated, in months, as: (Date of first PD (Progressive Disease) or death or censoring - date of first intratumoral injection + 1) / 30.4375. PD was defined, based on the protocol-defined criteria for response in For-Injection tumors, as at least a 20% increase in the longest diameter (LD) of the injected lesions, taking as reference the smallest LD recorded on study (this includes the baseline LD if that is the smallest on study; note: appearance of one or more new lesions was considered progression in assessing overall tumor response.). PFS derivation did not include tumor assessments collected after the end of study treatment as these were not planned for collection beyond the final cycle.
Time frame: up to 7 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ad/PNP + Fludarabine Phosphate, 5 Cycles | Progression Free Survival (PFS) - Time From First Intratumoral Injection to Date of Progression or Death, Calculated in Months | 7.0 Months |