Chemotherapy and Locoregional Therapy Trial (Surgery or Radiation) for Patients With Head and Neck Cancer (OPTIMA-II)

• ClinicalTrials.gov Identifier: NCT03107182
• Recruitment Status: Active, not recruiting
• First Posted: April 11, 2017
• Last Update Posted: September 17, 2020
• Sponsor: University of Chicago
• Information provided by (Responsible Party): University of Chicago

Tracking Information

• First Submitted Date: March 29, 2017
• First Posted Date: April 11, 2017
• Last Update Posted Date: September 17, 2020
• Actual Study Start Date: June 27, 2017
• Estimated Primary Completion Date: July 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 4, 2017)

Evaluate the tumor shrinkage (%) to measure the deep response rate (DRR) [ Time Frame: 24 months ]

DRR is defined as ≥50% tumor shrinkage by RECIST 1.1. We will evaluate the overall percentage of patients treated with dose-reduced radiotherapy or TORS to determine the tumor shrinkage based on treatment received.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 4, 2017)

• number of patients with adverse events [ Time Frame: 24 months ]
  All recorded adverse events will be listed and tabulated by system organ class, preferred term and treatment. Vital signs and clinical laboratory test results will be listed and summarized by treatment. Any significant physical examination findings, and clinical laboratory results will be listed. ECG readings will be evaluated by the investigator and abnormalities, if present, will be listed.
• to measure the 2 year progression-free survival (PFS) [ Time Frame: From start date of therapy to the date of first documented disease progression or death from any cause, whichever may come first, assessed up to 24 months ]
• to measure the 2 year overall survival (OS) [ Time Frame: From start date of therapy to the date of documented death, assessed up to 24 months ]
• to measure the 2 year rates of locoregional and distant control [ Time Frame: 24 months ]
  Time to locoregional and distant failure rates will be estimated by the Kaplan-Meier methodology and comparisons will be made using the log-rank test.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Chemotherapy and Locoregional Therapy Trial (Surgery or Radiation) for Patients With Head and Neck Cancer
• Official Title: A Phase II Trial of Nivolumab/Nab-paclitaxel/Carboplatin Induction Chemotherapy Followed by Response-stratified Locoregional Therapy for Patients With Locoregionally Advanced HPV-related Oropharyngeal Cancer- the OPTIMA II Trial

Brief Summary

Carboplatin, nab-paclitaxel, and nivolumab combination will be administered for three cycles of three weeks duration each. TORS or RT/CRT will be performed after induction chemotherapy (i.e. day 64 of therapy). Patients with low risk and small volume tonsillar disease (T1-T2, non-bulky N2A-N2B with ≤2 non-lower neck lymph nodes measuring ≤5 cm in size) or base of tongue disease (T1-2 with lateralized primary ≤3 cm, non-bulky N2A-N2B with ≤2 non-lower neck lymph nodes measuring ≤5 cm in size) who have ≥50% reduction by RECIST following induction chemotherapy will undergo TORS and selective nodal dissection. De-intensified adjuvant RT will be given for adverse pathologic features. Patients may refuse TORS treatment.

Patients with low risk, who do not qualify for TORS (due to volume of disease or poor visualization/access) or refuse TORS, who have ≥50% reduction by RECIST following induction chemotherapy will be given de-intensified treatment with radiation alone to 50 Gy.

Before induction chemotherapy, patients will undergo examination under anesthesia and direct laryngoscopy to tattoo and photograph the primary tumor to plan the post-induction resection. Adjuvant nivolumab will be offered to all patients for 6-months post completion of definitive therapy (7 doses given as a flat dose of 480mg, every four weeks).

• Detailed Description: A phase II trial in human papillomavirus (HPV)-positive oropharyngeal squamous cell cancer (as determined by p16 immunohistochemistry with confirmatory ISH or PCR) to determine radiologic response to induction chemotherapy with nivolumab. Patients will undergo evaluation by a multidisciplinary team prior to risk assessment. The patients will be assigned to high or low risk groups based on tumor size, lymph node involvement, and smoking history. Patients will be assigned to treatment with induction chemotherapy with carboplatin, nab-paclitaxel, and nivolumab. Radiologic response to induction chemotherapy according to RECIST measurement of tumor shrinkage will then be used for therapeutic stratification of locoregional therapy, consisting of either transoral robotic surgery (TORS) or radiation with or without chemotherapy. Patients with low risk disease (see table above) and small volume tonsillar/BOT disease (T1-2 primary, non-bulky N2A-N2B nodal status) who have ≥50% reduction by RECIST following induction chemotherapy will undergo TORS for primary site resection and selective nodal dissection as a definitive treatment if technically feasible with adjuvant radiation for adverse pathologic features. Patients with other low risk tumors e.g. with higher volume disease, or who refuse surgery, who also have ≥50% reduction by RECIST following induction chemotherapy will be given de-intensified treatment with radiation alone to 50 Gy (no chemotherapy). Patients with low risk features and <50% but ≥30% reduction OR high risk features (T4, bulky N2B or N2C-N3, >10 pack-years tobacco use) with ≥50% reduction will receive de-intensified chemoradiation with concurrent cisplatin-RT to 50 Gy (5 weeks) or TFHX to 45 Gy (3 cycles/6 weeks). Patients with low risk features and <30% reduction OR high risk disease with <50% reduction or any patients with progressive disease during induction chemotherapy will undergo chemoradiotherapy with concurrent cisplatin-RT to 70 Gy (7 weeks) or TFHX to 75 Gy (5 cycles/10 weeks). Patients with both high and low risk features who have ≥50% reduction will receive locoregional therapy targeting the pre-chemotherapy extent of disease only. Adjuvant nivolumab will be offered to all patients for 6-months post completion of definitive therapy (7 doses given as a flat dose of 480mg, every four weeks).
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• HPV-Related Squamous Cell Carcinoma
• HNSCC

Intervention

• Drug: nab-paclitaxel
  All enrolled patients will receive three 21-day cycles of nab-paclitaxel (100 mg/m2 on days 1, 8, 15; 9 doses total)
  Other Names:

  • nanoparticle albumin-bound paclitaxel
  • Abraxane
• Drug: Carboplatin
  All enrolled patients will receive three 21-day cycles of carboplatin (AUC 6 on day 1; 3 doses total).
  Other Name: paraplatin
• Drug: Nivolumab

  All enrolled patients will receive three 21-day cycles of nivolumab (360 mg on days 1; 3 doses total).

  Adjuvant nivolumab will be offered to all patients for 6-months post completion of locoregional therapy for a total of 7 doses.

  Other Name: Opdivo
• Drug: Cisplatin
  Cisplatin will be given on an every 3 weeks basis at a dose of 100 mg/m2 IV over 3-4 hrs day 1 (or 2) and 22 (or 23). Only for patients on the Intermediate Dose Arm and additionally on day 43 (or 44) for patients on the Regular Dose Arm.
  Other Name: platinol
• Drug: Hydroxyurea
  Patients on the Intermediate or Regular Dose Arms will receive chemoradiation for 3-5 cycles (6-10 weeks). On day 0 patients will start hydroxyurea at 500 mg PO q 12 hours x 6 days (11 doses). The first daily dose of hydroxyurea on days 1 - 5 is given 2 hours prior to the first fraction of daily radiotherapy.
• Drug: 5-FU
  Patients on the Intermediate or Regular Dose Arms will receive chemoradiation for 3-5 cycles (6-10 weeks). On day 0 at 1800 patients will start continuous infusion of 5-FU at 600 mg/m2/day x 5 days (120 hours).
  Other Names:

  • Adrucil
  • Carac
• Drug: Dexamethasone
  Patients on the Intermediate or Regular Dose Arms will receive chemoradiation for 3-5 cycles (6-10 weeks). On days 1-5 patients will receive dexamethasone 20 mg PO (IV) in am Day 1, 1 hr prior to paclitaxel
• Drug: Famotidine
  Patients on the Intermediate or Regular Dose Arms will receive chemoradiation for 3-5 cycles (6-10 weeks). On days 1-5 patients will receive famotidine 20 mg PO (IV) in am Day 1, 1 hr prior to paclitaxel.
  Other Name: pepcid
• Drug: Diphenhydramine
  Patients on the Intermediate or Regular Dose Arms will receive chemoradiation for 3-5 cycles (6-10 weeks). On days 1-5 patients will receive diphenhydramine 50 mg PO (IV) in am Day 1, 30 mins prior to paclitaxel.
  Other Name: benadryl
• Drug: Paclitaxel
  Patients on the Intermediate or Regular Dose Arms will receive chemoradiation for 3-5 cycles (6-10 weeks). On days 1-5 patients will start paclitaxel 100 mg/m2 after first RT fraction on day 1 of each cycle. Paclitaxel should be administered in 250 ml 0.9% NaCl over 60 minutes.
  Other Name: taxol
• Procedure: Transoral robotic surgery (TORS)
  Patients with low risk and small volume tonsillar disease (T1-T2, non-bulky N2A-N2B with ≤2 non-lower neck lymph nodes measuring ≤5 cm in size) or base of tongue disease (T1-2 with lateralized primary ≤3 cm, non-bulky N2A-N2B with ≤2 non-lower neck lymph nodes measuring ≤5 cm in size) who have ≥50% reduction by RECIST following induction chemotherapy will undergo TORS and selective nodal dissection. Patients may refuse TORS treatment. Patients will receive RT or TORS.
  Other Name: TORS
• Radiation: Adjuvant RT
  Patients with low risk, who do not qualify for TORS (due to volume of disease or poor visualization/access) or refuse TORS, who have ≥50% reduction by RECIST following induction chemotherapy will be given de-intensified treatment with radiation alone to 50 Gy. Patients will receive RT or TORS.
  Other Name: RT
• Radiation: Chemoradiotherapy

  Patients who have low risk disease with <50% but ≥30% reduction, or patients who have high risk disease and ≥50% reduction of tumor by RECIST with induction chemotherapy will receive CRT to 50 Gy with concurrent bolus cisplatin (x2 doses) or TFHX to 45 Gy (3 cycles).

  Patients who have low risk disease and <30% reduction of tumor, patients who have high risk disease and <50% reduction of tumor by RECIST, or any patient who has progressive disease with induction chemotherapy will receive CRT to 70 Gy with concurrent bolus cisplatin (x3 doses) or TFHX to 75 Gy (5 cycles).

  Other Name: CRT

Study Arms

• Experimental: Induction Chemotherapy

  All enrolled patients will receive three 21-day cycles of chemotherapy consisting of nab-paclitaxel (100 mg/m2 on days 1, 8, 15; 9 doses total), carboplatin (AUC 5 on day 1; 3 doses total), and nivolumab (360 mg on days 1; 3 doses total). Growth factor support will be provided using G-CSF administered on days 16-18.

  Adjuvant nivolumab will be offered to all patients for 6-months post completion of locoregional therapy.

  Interventions:

  • Drug: nab-paclitaxel
  • Drug: Carboplatin
  • Drug: Nivolumab
• Experimental: Single Modality De-escalation Arm (SDA)

  Following the induction treatments (carboplatin, nab-paclitaxel, and nivolumab), patients will be assessed based on response to chemotherapy and high or low risk status.

  Patients with low risk and small volume tonsillar disease (T1-T2, non-bulky N2A-N2B with ≤2 non-lower neck lymph nodes measuring ≤5 cm in size) or base of tongue disease (T1-2 with lateralized primary ≤3 cm, non-bulky N2A-N2B with ≤2 non-lower neck lymph nodes measuring ≤5 cm in size) who have ≥50% reduction by RECIST following induction chemotherapy will undergo TORS and selective nodal dissection. De-intensified adjuvant RT will be given for adverse pathologic features. Patients may refuse TORS treatment.

  Patients with low risk, who do not qualify for TORS (due to volume of disease or poor visualization/access) or refuse TORS, who have ≥50% reduction by RECIST following induction chemotherapy will be given de-intensified treatment with radiation alone to 50 G.

  Interventions:

  • Drug: Nivolumab
  • Procedure: Transoral robotic surgery (TORS)
  • Radiation: Adjuvant RT
• Experimental: Intermediate De-escalation Arm (IDA)

  Following the induction treatments (carboplatin, nab-paclitaxel, and nivolumab), patients will be assessed based on response to chemotherapy and high or low risk status.

  Patients who have low risk disease with <50% but ≥30% reduction of tumor by RECIST with induction chemotherapy will receive CRT to 50 Gy with concurrent bolus cisplatin (x2 doses) or TFHX (paclitaxel, 5-FU, hydroxyurea, dexamethasone, famotidine, and diphenhydramine) to 45 Gy (3 cycles).

  Patients who have high risk disease and ≥50% reduction of tumor by RECIST with induction chemotherapy will receive CRT to 50 Gy with concurrent bolus cisplatin (x2 doses) or TFHX to 45 Gy (3 cycles).

  Interventions:

  • Drug: Nivolumab
  • Drug: Cisplatin
  • Drug: Hydroxyurea
  • Drug: 5-FU
  • Drug: Dexamethasone
  • Drug: Famotidine
  • Drug: Diphenhydramine
  • Drug: Paclitaxel
  • Radiation: Chemoradiotherapy
• Experimental: Regular Dose Arm (RDA)

  Following the induction treatments (carboplatin, nab-paclitaxel, and nivolumab), patients will be assessed based on response to chemotherapy and high or low risk status.

  Patients who have low risk disease and <30% reduction of tumor by RECIST with induction chemotherapy will receive CRT to 70 Gy with concurrent bolus cisplatin (x3 doses) or TFHX (paclitaxel, 5-FU, hydroxyurea, dexamethasone, famotidine, and diphenhydramine) to 75 Gy (5 cycles).

  Patients who have high risk disease and <50% reduction of tumor by RECIST with induction chemotherapy will receive CRT to 70 Gy with concurrent bolus cisplatin (x3 doses) or TFHX to 75 Gy (5 cycles).

  Any patient who has progressive disease will receive CRT to 70 Gy with concurrent bolus cisplatin (x3 doses) or TFHX to 75 Gy (5 cycles).

  Interventions:

  • Drug: Nivolumab
  • Drug: Cisplatin
  • Drug: Hydroxyurea
  • Drug: 5-FU
  • Drug: Dexamethasone
  • Drug: Famotidine
  • Drug: Diphenhydramine
  • Drug: Paclitaxel
  • Radiation: Chemoradiotherapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 15, 2020): 76
• Original Estimated Enrollment (submitted: April 4, 2017): 56
• Estimated Study Completion Date: July 2023
• Estimated Primary Completion Date: July 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients must have pathologically confirmed HPV-positive head and neck squamous cell carcinoma of the oropharynx. Confirmed HPV-positive disease of other subsites are uncommon but also eligible.
• HPV testing must be compliant with the following criteria:
• p16 IHC positivity is sufficient to enroll and initiate treatment (p16 IHC interpretation to follow guidelines by Jordan and Lingen et al89).
• p16 IHC positivity is to be validated using an HPV PCR during the induction phase. This is essential as HPV genotype influences treatment arm allocation, with non-HPV16 HPV strains being considered high risk.
• Availability of ≥10 unstained 5 micron slides (to be provided to HTRC at the University of Chicago). Patients who cannot fulfill this requirement will need to undergo a new biopsy prior to enrollment on study.
• Patients must be at least 18 years of age.
• Patients with AJCC (7th edition, 2010) N2-N3 nodal disease or T3-T4 primary tumor.
• Measurable disease (either primary site and/or nodal disease) by RECIST 1.1 criteria.
• No previous radiation or chemotherapy for a head and neck cancer.
• No complete surgical resection for a head and neck cancer within 8 weeks of enrollment (although lymph node biopsy including excision of an individual node with presence of residual nodal disease, or surgical biopsy/excision of the tumor with residual disease is acceptable).
• ECOG performance status 0-1 (Karnofsky greater than or equal to 80%).
• Normal Organ Function
• Leukocytes ≥3000/mm3,
• platelets ≥100,000/mm3,
• absolute neutrophil count ≥1,500,
• hemoglobin >9.0 gm/dL,
• AST and ALT <2.5 X ULN
• alkaline phosphatase <2.5 X ULN
• albumin >2.9 gm/dL, 29 Version Date: 12/28/2016
• total bilirubin ≤1.5 mg/dl,
• creatinine clearance >45 mL/min (or SCr <1.5 mg/dL), normal within 2 weeks prior to start of treatment.
• The standard Cockcroft and Gault formula or the measured glomerular filtration rate must be used to calculate CrCl for enrollment or dosing
• Patients must sign a study-specific informed consent form prior to study entry. Patients should have the ability to understand and the willingness to sign a written informed consent document.

• Age, Sex, and Reproductive Status:

  1. Men and women, ages > 18.
  2. Women of childbearing potential (WOCBP=premenopausal woman capable of becoming pregnant) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
  3. Women must not be breastfeeding.
  4. WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 half-lives of study drug(s) plus 30 days (duration of ovulatory cycle) for a total of 23 weeks post-treatment completion.
  5. Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 half-lives of study drug(s) plus 90 days (duration of sperm turnover) for a total of 31 weeks post treatment completion.
  6. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, they must still undergo pregnancy testing as described in this section.
• Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of <1% when used consistently and correctly.
• At a minimum subjects must agree to the use of one method of highly effective contraception as listed below:

HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

• Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) such as Mirena® by WOCBP subject or male subject's WOCBP partner
• IUDs, such as ParaGard®
• Tubal ligation
• Vasectomy 30 Version Date: 12/28/2016

• Complete Abstinence*

  • *Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an acceptable form of contraception for all study drugs. Female subjects must continue to have pregnancy tests. Acceptable alternate methods of highly effective contraception must be discussed in the event that the subject chooses to forego complete abstinence.

Subjects are encouraged to use two methods of contraception, with one method being highly effective and the other method being either highly effective or less effective as listed below:

LESS EFFECTIVE METHODS OF CONTRACEPTION

• Diaphragm with spermicide
• Cervical cap with spermicide
• Vaginal sponge
• Male condoms and spermicide
• Male condom without spermicide
• Progestin only pills by WOCBP subject or male subject's WOCBP partner

• Female condom*

  • *A male and female condom must not be used together

Exclusion Criteria:

• Unequivocal demonstration of distant metastases (M1 disease).
• Unidentifiable primary site.
• Intercurrent medical illnesses which would impair patient tolerance to therapy or limit survival. Including but not limited to ongoing or active infection, immunodeficiency, symptomatic congestive heart failure, pulmonary dysfunction, cardiomyopathy, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance.
• Pregnant and nursing women are excluded because of the potential teratogenic effects and potential unknown effects on nursing newborns (please see above paragraph under inclusion criteria regarding WOCBP) 31 Version Date: 12/28/2016
• Prior surgical therapy other than incisional/excisional biopsy or organ-sparing procedures such as debulking of airway-compromising tumors. Residual measurable tumor is required for enrollment on study as outlined above
• Patients receiving other investigational agents.
• Peripheral neuropathy >grade 1
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy in excess of physiologic dose or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
• Has a known history of active tuberculosis (Bacillus Tuberculosis infection)
• Has hypersensitivity to nivolumab or any other drug used in this protocol.
• Has had a prior systemic anti-cancer treatment within the last 8 weeks
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer or any tumors that are not likely to influence live expectancy in the subsequent 3 years without active treatment (e.g. low grade prostate cancer in absence of therapy).
• Has active autoimmune disease that has required systemic treatment in the past year (i.e. with use of steroids or immunosuppressive drugs). Replacement therapy e.g. levothyroxine, insulin, or physiologic corticosteroid doses for adrenal or pituitary insufficiency, etc. are not considered a form of systemic treatment.
• Has known history of, or any evidence of active, non-infectious pneumonitis.
• Has a history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). However, if eradicated patient is eligible.
• Has received a live vaccine within 28 days of planned start of study therapy. o Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed within 28 days prior to initiation of treatment.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03107182
• Other Study ID Numbers: IRB17-0104
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: University of Chicago
• Study Sponsor: University of Chicago
• Collaborators: Not Provided

Investigators

• Principal Investigator: Tanguy Seiwert, MD; University of Chicago

• PRS Account: University of Chicago
• Verification Date: September 2020