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

The Washington University

Status and phase: Completed; Phase 2

Conditions: Cancer of the Head and Neck; Neoplasms, Head and Neck; Squamous Cell Carcinoma of the Head and Neck; Cancer of Head and Neck; Carcinoma, Squamous Cell of the Head and Neck; Head and Neck Cancer

Treatments: Radiation: Intensity-Modulated Radiation Therapy; Drug: Cisplatin; Biological: Cetuximab; Drug: nab-Paclitaxel

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT02573493

201510013

Details and patient eligibility

About

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.

Enrollment: 96 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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96 participants in 3 patient groups

Arm 1: nab-Paclitaxel and cisplatin (AP) + CRT

Experimental group

Description:

* Six 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.

Treatment:

Drug: nab-Paclitaxel

Drug: Cisplatin

Radiation: Intensity-Modulated Radiation Therapy

Arm 2: nab-Paclitaxel (A) + CRT

Experimental group

Description:

* Six 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.

Treatment:

Drug: nab-Paclitaxel

Biological: Cetuximab

Radiation: Intensity-Modulated Radiation Therapy

Arm 3: nab-Paclitaxel and cisplatin (AP) + modified CRT

Experimental group

Description:

* 6 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.

Treatment:

Drug: nab-Paclitaxel

Drug: Cisplatin

Radiation: Intensity-Modulated Radiation Therapy