Mitomycin C in Patients With Incurable p16 Positive Oropharyngeal and p16 Negative Head and Neck Squamous Cell Carcinoma (HNSCC) Resistant to Standard Therapies

Study Overview
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Brief Summary
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No agent is known to have efficacy in patients with incurable HNSCC that progressed with prior platin, 5-FU, cetuximab and taxane. Herein lies the unmet need to be addressed by this trial. Based on the preclinical and clinical data presented, the investigators propose that mitomycin C will have anti-tumor activity in these patients.

Official Title
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Phase II Trial of Mitomycin C in Patients With Incurable p16 Positive Oropharyngeal and p16 Negative Head and Neck Squamous Cell Carcinoma (HNSCC) Resistant to Standard Therapies

Conditions
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Squamous Cell Carcinoma of the Head and Neck, Squamous Cell Carcinoma, Head and Neck

Intervention / Treatment
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* Drug: Mitomycin-C
* Drug: Pegfilgrastim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed incurable HNSCC of the oral cavity, oropharynx, larynx, hypopharynx, and/or Level 1-3 neck node with non-cutaneous SCC and unknown primary. Incurable is defined as metastatic disease or a local or regional recurrence in a previously irradiated site that is unresectable (or patient declines resection). Progression following platin and immunotherapy given for incurable disease. Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam per RECIST 1.1. Tissue available (either initial diagnostic or recurrent tissue specimen) for p16 testing. At least 18 years of age. ECOG performance status ≤ 3 Adequate hematologic, renal, and hepatic function as defined below: Absolute neutrophil count ≥ 1,000/mcl Platelets ≥ 75,000/mcl Total bilirubin ≤ 1.5 mg/dL AST(SGOT)/ALT(SGPT) ≤ 2.5 x ULN, alkaline phosphatase ≤ 2.5 x ULN, unless bone metastasis is present in the absence of liver metastasis Creatinine below ULN (males 0.7-1.30 mg/dl; females 0.6-1.10 mg/dl) OR Creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, for the duration of study participation, and for 1 month after completing treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Exclusion Criteria: Other active malignancy with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only, carcinoma in situ of the cervix, or synchronous H&N primaries. Currently receiving any other investigational agents. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant and/or breastfeeding. Patient must have a negative pregnancy test within 7 days of start of study treatment. Known active central nervous system (CNS) metastases. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment 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 28 days prior to treatment. A history of allergic reactions attributed to compounds of similar chemical or biologic composition to mitomycin C or other agents used in the study. Known HIV-positivity on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with the study drugs. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: p16+ OPSCC<br>Mitomycin C given on Day 1 every 5 weeks (each cycle is 5 weeks). Pegfilgrastim will be given on Day 2 of each cycle (subcutaneous injection) | Drug: Mitomycin-C<br> <br> * Other names: Mitomycin;Drug: Pegfilgrastim<br> <br> * Other names: GCSF;|
| Experimental: Cohort 2: p16- HNSCC<br>Mitomycin C given on Day 1 every 5 weeks (each cycle is 5 weeks). Pegfilgrastim will be given on Day 2 of each cycle (subcutaneous injection) | Drug: Mitomycin-C<br> <br> * Other names: Mitomycin;Drug: Pegfilgrastim<br> <br> * Other names: GCSF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response Rate (TRR) | TRR will be evaluated separately in p16- (HPV-unrelated) HNSCC patients and in p16+ (HPV positive) OPSCC patients using two optimal two-stage Simon designs. In both cases, the expected TRR is 10%. A TRR of 30% is considered a clinically significant increase. RECIST 1.1 will be used for this outcome. | Approximately 6 months (median 5.6 months with full range of 0.1-33.7 months) | 
| Tumor Response Rate (TRR) for Participants Enrolled Post October 2020 | TRR will be evaluated in p16+ (HPV positive) OPSCC HNSCC patients RECIST 1.1 will be used for this outcome. | Approximately 6 months (median 4.0 months with full range of 0.5-12.0 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS is defined as the duration of time from start of treatment to time of first radiologic confirmation of progression or death, whichever occurs first. Progressive disease per RECIST 1.1 Target lesions - At least a 20% increase in the sum of the 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. Non-target lesions - Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. | Approximately 6 months (median 5.6 months with full range of 0.1-33.7 months) | 
| Number of Participants With Grade 3/4/5 Adverse Events | -Using CTCAE Version 3.0 | 28 days after completion of treatment (median length of follow-up was 98 days, full range of 31-463 days) | 
| Overall Survival (OS) |  | Approximately 11 months (due to estimated OS of 10.1 months) |