Clinical Trials /

Nab-Paclitaxel and Cisplatin or Nab-paclitaxel as Induction Therapy for Locally Advanced Squamous Cell Carcinoma of the Head and Neck (HNSCC)

NCT02573493

Description:

In this trial, the objectives are to determine the efficacy and toxicity of induction chemotherapy (IC) with nab-paclitaxel + cisplatin (Arm 1: AP) and with nab-paclitaxel (Arm 2: A) alone in patients with HNSCC, and to compare these data to nab-paclitaxel, cisplatin, and 5-FU (APF). The investigators also hypothesize that the high anti-tumor efficacy of nab-paclitaxel in HNSCC is due to the upregulation of macropinocytosis, a result of the frequent presence of Ras and PI3K (and epidermal growth factor receptor -EGFR) activation in this cancer. Amendment to Add Arm 3: In this amendment, the investigators retain the AP + concurrent chemoradiation therapy (CRT) backbone but de-escalate the dose of radiation therapy (RT) from 70 Gy to 42 Gy. The investigators also plan to administer one dose (vs three) of cisplatin during RT. This novel treatment approach will be evaluated in patients with HPV-related oropharyngeal squamous cell carcinoma (OPSCC) (Arm 3), a sub-group with a very favorable prognosis.

Related Conditions:
  • Hypopharyngeal Squamous Cell Carcinoma
  • Laryngeal Squamous Cell Carcinoma
  • Oropharyngeal Squamous Cell Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nab-Paclitaxel and Cisplatin or Nab-paclitaxel as Induction Therapy for Locally Advanced Squamous Cell Carcinoma of the Head and Neck (HNSCC)
  • Official Title: Phase II Non-Randomized Three Arm Trial of Induction Chemotherapy With Nab-Paclitaxel and Cisplatin (AP: Arms 1 and 3) or Single Agent Nab-paclitaxel (A: Arm 2) as Induction Therapy Followed by Definitive Concurrent Chemoradiation for Locally Advanced Squamous Cell Carcinoma of the Head and Neck (HNSCC): "The APA Trial".

Clinical Trial IDs

  • ORG STUDY ID: 201510013
  • NCT ID: NCT02573493

Conditions

  • Squamous Cell Carcinoma of the Head and Neck
  • Carcinoma, Squamous Cell of the Head and Neck
  • Cancer of Head and Neck
  • Cancer of the Head and Neck
  • Head and Neck Cancer
  • Neoplasms, Head and Neck

Interventions

DrugSynonymsArms
nab-PaclitaxelAbraxaneArm 1: nab-Paclitaxel and cisplatin (AP) + CRT
Cisplatincis-DDP, cis-Platinum II, cis-Diamminedichloroplatinum, DDPArm 1: nab-Paclitaxel and cisplatin (AP) + CRT
CetuximabErbitux®Arm 2: nab-Paclitaxel (A) + CRT

Purpose

In this trial, the objectives are to determine the efficacy and toxicity of induction chemotherapy (IC) with nab-paclitaxel + cisplatin (Arm 1: AP) and with nab-paclitaxel (Arm 2: A) alone in patients with HNSCC, and to compare these data to nab-paclitaxel, cisplatin, and 5-FU (APF). The investigators also hypothesize that the high anti-tumor efficacy of nab-paclitaxel in HNSCC is due to the upregulation of macropinocytosis, a result of the frequent presence of Ras and PI3K (and epidermal growth factor receptor -EGFR) activation in this cancer. Amendment to Add Arm 3: In this amendment, the investigators retain the AP + concurrent chemoradiation therapy (CRT) backbone but de-escalate the dose of radiation therapy (RT) from 70 Gy to 42 Gy. The investigators also plan to administer one dose (vs three) of cisplatin during RT. This novel treatment approach will be evaluated in patients with HPV-related oropharyngeal squamous cell carcinoma (OPSCC) (Arm 3), a sub-group with a very favorable prognosis.

Trial Arms

NameTypeDescriptionInterventions
Arm 1: nab-Paclitaxel and cisplatin (AP) + CRTExperimentalSix weeks of nab-paclitaxel (100 mg/m2/week) and cisplatin (75 mg/m2 days 1 and 22) followed by primary tumor site (PTS) assessment If complete response (CR)/partial response (PR), three more weeks of nab-paclitaxel and cisplatin followed by concurrent chemoradiation therapy (CRT) If <PR, move directly to CRT if not surgical candidates. CRT includes cisplatin which will begin 1 to 35 days after the completion of cycle 3. The first dose of cisplatin will be given during the initial 5 days of definitive radiation therapy, the second on approximately Day 22 of radiation, and the third on approximately Day 43 of radiation. It is strongly recommended that intensity-modulated radiation therapy (IMRT) begin within 21 to 42 days (no later than 56 days) after the start of cycle 3. The total dose will be 7000 cGy in 35 fractions of 200 cGy each over 7 weeks. A dose of 6300 cGy in 35 fractions is optional and may be delivered to areas considered to be an intermediate risk.
  • nab-Paclitaxel
  • Cisplatin
Arm 2: nab-Paclitaxel (A) + CRTExperimentalSix weeks of nab-paclitaxel (100 mg/m2/week) followed by primary tumor site (PTS) assessment If CR/PR, three more weeks of nab-paclitaxel followed by CRT If <PR, move directly to CRT if not surgical candidates. CRT includes cetuximab and will begin 1 to 35 days after completion of cycle -Cetuximab will be started 7 days before starting definitive radiation therapy. The initial loading dose of cetuximab will be 400 mg/m^2. Subsequently, cetuximab will be given weekly at a dose of 250 mg/m^2 for seven additional doses concurrently with radiation therapy. It is strongly recommended that IMRT begin within 21 to 42 days (no later than 56 days) after the start of cycle 3. The total dose will be 7000 cGy in 35 fractions of 200 cGy each over 7 weeks. A dose of 6300 cGy in 35 fractions is optional and may be delivered to areas considered to be an intermediate risk.
  • nab-Paclitaxel
  • Cetuximab
Arm 3: nab-Paclitaxel and cisplatin (AP) + modified CRTExperimental6 weeks of nab-paclitaxel and cisplatin (days 1 & 22) followed by primary tumor site assessment If CR/PR, cycle 3 of induction then 42Gy radiation, 1 dose of cisplatin or 6 doses cetuximab If SD/PD: undergo surgery if candidate followed by CRT with 42 Gy RT and abbreviated cisplatin or cetuximab or 70Gy RT and 3 cycles of cisplatin or 8 doses of cetuximab CRT includes Cisplatin and will begin 1-35 days after the completion of Cycle 3 of induction. Cisplatin will be given as 1 dose during the initial 5 days of definitive radiation therapy Strongly recommended that radiation therapy begin within 28-49 days (and no later than 56 days) after the start of Cycle 3. Intensity modulated radiation therapy is to be used exclusively for this study.
  • nab-Paclitaxel
  • Cisplatin

Eligibility Criteria

        Inclusion Criteria: Arms 1 and 3 - AP

          -  Diagnosis of selected Stage III or IVa/b HNSCC. Arm 1: T2-T4 primary tumors. Arm 3:
             T2T1-T4 primary tumors. Although most of these patients will have regional nodal
             disease, patients with no nodal disease will also be eligible.

          -  Arm 1: Presence of disease at the oropharynx, hypopharynx, or larynx sub-sites.

          -  Arm 3: Presence of disease at the oropharynx sub-sites, which is HPV-related as
             verified by p16, a surrogate marker of HPV, or HPV ISH or PCR.

          -  Presence of 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.

          -  At least 18 years of age.

          -  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 3 months 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.

          -  Able to understand and willing to sign an IRB-approved written informed consent
             document.

          -  ECOG performance status ≤ 1.

          -  Adequate bone marrow and organ function as defined below:

               -  ANC: ≥ 1500/mcL.

               -  Platelets: > 100,000/mcL.

               -  Hemoglobin > 9.0 g/dL

               -  Total bilirubin ≤ 1.5 mg/dL

               -  AST/ALT/alkaline phosphatase: ≤ 2.5 x ULN.

               -  Serum creatinine: < 1.5 mg/dL or calculated GFR ≥ 75 cc/min. CrCl by Cockcroft
                  Gault will be used to estimate GFR.

               -  Pulmonary: no requirement for supplemental oxygen and no evidence of
                  moderate-severe chronic obstructive pulmonary disease (COPD) by pulmonary
                  function tests (PFTs).

        Inclusion Criteria: Arm 2 - A

          -  Diagnosis of selected Stage III or IVa/b HNSCC. T2-T4 primary tumors. (Patients with
             T1 tumors will be excluded). Although most of these patients will have regional nodal
             disease, patients with no nodal disease will also be eligible.

          -  Presence of disease at the oropharynx, hypopharynx, or larynx sub-sites.

          -  Presence of 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.

          -  At least 18 years of age.

          -  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 3 months 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.

          -  Able to understand and willing to sign an IRB-approved written informed consent
             document.

          -  ECOG performance status < 3.

          -  Adequate bone marrow and organ function as defined below:

               -  ANC: ≥ 1500/mcL.

               -  Platelets: ≥ 100,000/mcL.

               -  Hemoglobin > 9.0 g/dL

               -  Total bilirubin ≤ 2.0 mg/dL

               -  AST/ALT/alkaline phosphatase: ≤ 5x ULN.

               -  Calculated GFR >30 cc/min. CrCl by Cockcroft Gault will be used to estimate GFR.

               -  Pulmonary: patients with a requirement for supplemental oxygen or evidence of
                  moderate-severe COPD by PFTs are permitted to enroll.

          -  If a patient fully meets criteria for Arm 1, but has profound hearing loss and the
             physician feels that the patient should not receive Cisplatin, the patient will be
             eligible for Arm 2.

          -  If a patient fully meets criteria for Arm 1, but has a history of solid organ or bone
             marrow transplant, the patient will be eligible for Arm 2 (due to contraindications of
             Cisplatin with medications the patient is taking due to the transplant).

        Exclusion Criteria (Arm 1 and Arm 2)

          -  Prior chemotherapy, prior EGFR targeted therapy, or prior radiation therapy for HNSCC.

          -  Disease at the nasopharyngeal, sinus, oral cavity, or other sub-site not specified as
             eligible.

          -  Diagnosis of unknown primary squamous cell carcinoma of the head and neck.

          -  History of prior invasive malignancy diagnosed within 3 years prior to study
             enrollment; exceptions are malignancies with a negligible risk of metastasis or death
             (e.g., expected 5-year OS > 90%) that were treated with an expected curative outcome,
             such as squamous cell carcinoma of the skin, in-situ carcinoma of the cervix uteri,
             non-melanomatous skin cancer, carcinoma in situ of the breast, or incidental
             histological finding of prostate cancer (TNM stage of T1a or T1b)

          -  Receiving any other investigational agents.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to any of the agents used in this study.

          -  Taking cimetidine or allopurinol. If currently taking either of these medications,
             patient must discontinue for one week before receiving treatment with nab-paclitaxel.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             serious infection, symptomatic congestive heart failure, unstable angina pectoris,
             cardiac arrhythmia, or serious psychiatric illness/social situations that would limit
             compliance with study requirements.

          -  Pregnant and/or breastfeeding. A negative serum or urine pregnancy test is required at
             screening for all female patients of childbearing potential.

          -  Known to be HIV-positive on combination antiretroviral therapy because of the
             potential for pharmacokinetic interactions with the study agents. 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.

          -  Peripheral neuropathy > grade 1.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Arm 1 and Arm 2: Complete response rate as measured by clinical exam at the primary tumor site
Time Frame:Completion of 2 cycles (approximately 6 weeks)
Safety Issue:
Description:Assessment of primary tumor site will be done by laryngoscopy performed in the office or in the operating room. The primary tumor response to the first two cycles of induction will be assessed using visual categorical response. The percent change from baseline will be dictated in the ear, nose, and throat (ENT) physician's clinical exam note. Complete response = complete resolution - 100% decrease/minimal residual mucosal abnormality

Secondary Outcome Measures

Measure:Arms 1, 2, and 3: Partial response rate as measured by clinical exam at the primary tumor site
Time Frame:Completion of 2 cycles (approximately 6 weeks)
Safety Issue:
Description:Assessment of primary tumor site will be done by laryngoscopy performed in the office or in the operating room. The primary tumor response to the first two cycles of induction will be assessed using visual categorical response. The percent change from baseline will be dictated in the ENT physician's clinical exam note. Partial response - 99-50% decrease
Measure:Arms 1, 2 and 3: Complete response rate as measured by clinical exam at the involved regional nodes
Time Frame:Completion of 2 cycles (approximately 6 weeks)
Safety Issue:
Description:The involved neck node response to the first two cycles of induction will be assessed using visual categorical response. The neck node measurements will be performed clinically by the treating medical oncology physician and dictated in his/her assessment note. Complete response - complete resolution - 100% decrease/minimal residual mucosal abnormality
Measure:Arms 1, 2, and 3: Partial response rate as measured by clinical exam at the involved regional nodes
Time Frame:Completion of 2 cycles (approximately 6 weeks)
Safety Issue:
Description:The involved neck node response to the first two cycles of induction will be assessed using visual categorical response. The neck node measurements will be performed clinically by the treating medical oncology physician and dictated in his/her assessment note. Partial response - 99%-50% decrease
Measure:Arms 1, 2, and 3: Anatomic tumor response as assessed by CT using RECIST 1.0 criteria
Time Frame:Completion of 2 cycles (approximately 6 weeks)
Safety Issue:
Description:-Computed tomography (CT) scan (intravenous contrast preferred) to document and measure the extent of the primary tumor size and involved regional neck nodes. RECIST 1.0 will be used to determine response at the primary tumor site, at the involved regional neck nodes and the radiographic overall tumor response.
Measure:Arms 1, 2, and 3: Document and quantify Ki-67 expression by IHC in primary tumor tissue and correlate with clinical primary tumor site response
Time Frame:Completion of 2 cycles (approximately 42 days)
Safety Issue:
Description:
Measure:Arms 1, 2, and 3: Grade 3-4 adverse events as measured by NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0
Time Frame:30 days after completion of treatment (estimated to be 15-25 weeks)
Safety Issue:
Description:compare to those observed with APF with the objective that Arm 1 will be at least 25% lower than the risk of Grade 3-4 AE's during APF (40% decreased to 30%) and Arm 2 will be at least 50% lower than the risk of Grade 3-4 AE's during APF (40% decreased to 20%).
Measure:Arms 1, 2, and 3: Overall survival (OS)
Time Frame:10 years
Safety Issue:
Description:OS: duration of time from start of treatment to time of death from any cause
Measure:Arms 1, 2, and 3: Disease-free survival (DFS)
Time Frame:10 years
Safety Issue:
Description:
Measure:Arms 1, 2, and 3: Progression-free survival (PFS)
Time Frame:10 years
Safety Issue:
Description:◦PFS: duration of time from start of treatment to time of progression or death, whichever occurs first.
Measure:Arms 1, 2, and 3: Quality of life as measured by FACT-H&N and FACT/GOG-NTX-4
Time Frame:Through one year after completion of treatment (approximately 74 weeks)
Safety Issue:
Description:The FACT/GOG-NTX-4 questionnaire has 4 questions with answers ranging from 0 (Not at all) to 4 (Very Much) The FACT-H&N has 5 sections including physical well-being, social/family well being, emotional well-being, functional well-being, and additional concerns. The answers range from 0 (Not at all) to 4 (Very Much)
Measure:Overall survival (OS) rate
Time Frame:1 year
Safety Issue:
Description:OS: duration of time from start of treatment to time of death from any cause
Measure:Overall survival (OS) rate
Time Frame:2 years
Safety Issue:
Description:OS: duration of time from start of treatment to time of death from any cause
Measure:Disease-free survival (DFS) rate
Time Frame:1 year
Safety Issue:
Description:
Measure:Disease-free survival (DFS) rate
Time Frame:2 years
Safety Issue:
Description:
Measure:Progression-free survival (PFS) rate
Time Frame:1 year
Safety Issue:
Description:◦PFS: duration of time from start of treatment to time of progression or death, whichever occurs first.
Measure:Progression-free survival (PFS) rate
Time Frame:2 years
Safety Issue:
Description:◦PFS: duration of time from start of treatment to time of progression or death, whichever occurs first.
Measure:Arm 3: Complete response rate as measured by clinical exam at the primary tumor site
Time Frame:Completion of 2 cycles (approximately 6 weeks)
Safety Issue:
Description:Assessment of primary tumor site will be done by laryngoscopy performed in the office or in the operating room. The primary tumor response to the first two cycles of induction will be assessed using visual categorical response. The percent change from baseline will be dictated in the ear, nose, and throat (ENT) physician's clinical exam note. Complete response = complete resolution - 100% decrease/minimal residual mucosal abnormality
Measure:Arm 1 and Arm 3: Comparison of response rate
Time Frame:Completion of 2 cycles (approximately 6 weeks)
Safety Issue:
Description:-Stratified for HPV status
Measure:Arm 1 and Arm 3: Comparison of overall survival
Time Frame:10 years
Safety Issue:
Description:-Stratified for HPV status
Measure:Arm 1 and Arm 3: Comparison of disease-free survival
Time Frame:10 years
Safety Issue:
Description:-Stratified for HPV status
Measure:Arm 1 and Arm 3: Comparison of progression-free survival
Time Frame:10 years
Safety Issue:
Description:-Stratified for HPV status
Measure:Arm 1 and Arm 3: Comparison of the rate of grade 3/4 adverse events
Time Frame:30 days after completion of treatment (estimated to be 15-25 weeks)
Safety Issue:
Description:
Measure:Comparison of median absolute weight loss in Arms 2 and 3 to Arm 1
Time Frame:Completion of treatment (estimated to be 11-21 weeks)
Safety Issue:
Description:
Measure:Comparison of median percent weight loss in Arms 2 and 3 to Arm 1
Time Frame:Completion of treatment (estimated to be 11-21 weeks)
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Washington University School of Medicine

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