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IRX-2 Regimen, Durvalumab, Tremelimumab for Incurable Head and Neck Squamous Cell Carcinoma

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ClinicalTrials.gov Identifier: NCT03381183
Recruitment Status : Not yet recruiting
First Posted : December 21, 2017
Last Update Posted : March 29, 2018
Sponsor:
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute

Brief Summary:
The purpose of this study is to see if the IRX-2 regimen, durvalumab, and tremelimumab will have a tolerable safety profile and will increase the intratumoral immune profile compared with the pretreatment tumors.

Condition or disease Intervention/treatment Phase
Squamous Cell Carcinoma Squamous Cell Carcinoma of the Head and Neck Metastatic Squamous Cell Carcinoma Oral Cavity Squamous Cell Carcinoma Oropharynx Squamous Cell Carcinoma Paranasal Sinus Squamous Cell Carcinoma Hypopharynx Squamous Cell Carcinoma Larynx Squamous Cell Carcinoma Drug: Durvalumab Drug: Tremelimumab Drug: IRX-2 Regimen Phase 1 Phase 2

Detailed Description:

Study Population:

Patients with histologically or cytologically confirmed recurrent or metastatic squamous cell carcinoma of oral cavity, oropharynx, paranasal sinuses, hypopharynx, or larynx that is not amenable to local therapy with curative intent. Squamous cell carcinoma of unknown primary in cervical lymph node can be included only if p16 status is positive.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b Trial of the IRX-2 Regimen, Durvalumab (MEDI4736), and Tremelimumab in Patients With Incurable Head and Neck Squamous Cell Carcinoma
Estimated Study Start Date : June 2018
Estimated Primary Completion Date : March 2020
Estimated Study Completion Date : March 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: Phase 1 - Dose Escalation
The dose escalation phase of the study will enroll 3 to 6 patients per dose level using a standard 3+3 design. Cohort 1 will be 3 participants enrolled at dose level 1. If no dose-limiting toxicities are observed during first 8 weeks of treatment, the enrollment will continue in dose expansion phase (expansion cohort at dose level 1). A dose limiting toxicity (DLT) will be defined as any Grade 3 or higher toxicity that occurs during the DLT evaluation period and are considered related to the combination of the IRX-2 regimen, durvalumab and tremelimumab (IDT) occurred during Cycle 1 Day 1 and Cycle 2 Day 28 (= 8 weeks). Toxicity that is clearly and directly related to the primary disease or to another etiology is excluded from this definition.
Drug: Durvalumab
Phase 1 and Phase 2: 1500 mg every 4 weeks (Q4wks).
Other Names:
  • MEDI4736
  • IMFINZI

Drug: Tremelimumab

Phase 1, Dose level 1 only: 75 mg Q4wks.

Phase 2, to be determined during Phase 1.

Other Name: CP-675,206

Drug: IRX-2 Regimen

Phase 1 and Phase 2 - Every 12 weeks - IRX-2 Regimen:

Cyclophosphamide 300 mg/m^2 - intravenously.

IRX-2: 460 units daily (4 injections of 115 units).


Experimental: Phase 2 - Dose Expansion
14-17 participants will be enrolled at the recommended dose level from the dose escalation phase, for a total enrollment of 20 participants; however, investigators will replace participants with any missing tumor sample collection and continue to the enrollment until there are 20 pre- and post-treatment paired tumors. The 3-6 participants treated at the maximum tolerated dose (MTD) in the dose escalation portion of the study will be counted as part of the dose expansion population.
Drug: Durvalumab
Phase 1 and Phase 2: 1500 mg every 4 weeks (Q4wks).
Other Names:
  • MEDI4736
  • IMFINZI

Drug: Tremelimumab

Phase 1, Dose level 1 only: 75 mg Q4wks.

Phase 2, to be determined during Phase 1.

Other Name: CP-675,206

Drug: IRX-2 Regimen

Phase 1 and Phase 2 - Every 12 weeks - IRX-2 Regimen:

Cyclophosphamide 300 mg/m^2 - intravenously.

IRX-2: 460 units daily (4 injections of 115 units).





Primary Outcome Measures :
  1. Phase 1 - Maximum Tolerated Dose (MTD) [ Time Frame: Up to 6 months ]
    MTD of combination of the IRX-2 regimen, durvalumab and tremelimumab (IDT) as outlined in treatment arm.


Secondary Outcome Measures :
  1. Phase 2 - Objective Clinical Response Rate of IDT [ Time Frame: Up to 12 months post treatment ]
    Response to combination of the IRX-2 regimen, durvalumab and tremelimumab (IDT). Objective response will be documented using standard Response Evaluation in Solid Tumors (RECIST) criteria.

  2. Phase 2 - Progression-free Survival (PFS) [ Time Frame: Up to 6 months post treatment ]
    PFS of IDT treatment participants at six months. Progression free survival is defined as the time from Day 1 of treatment to evidence of progression. Progression will be defined by RECIST v 1.1.

  3. Median Progression-free Survival [ Time Frame: Up to 12 months post treatment ]
    Median PFS of IDT treatment participants. Progression free survival is defined as the time from Day 1 of treatment to evidence of progression. Progression will be defined by RECIST v 1.1.

  4. Median Overall Survival (OS) [ Time Frame: Up to 12 months post treatment ]
    Median OS of IDT treatment participants. OS: The length of time from the start of treatment that participants are still alive.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participants must have histologically or cytologically confirmed squamous cell carcinoma of oral cavity, oropharynx, paranasal sinuses, hypopharynx, or larynx. Squamous cell carcinoma of unknown primary in cervical lymph node can be included only if p16 status is positive.
  • Must have recurrent or metastatic HNSCC stage III/IV that is not amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy).
  • Willing and able to give informed consent and adhere to protocol therapy; written informed consent and any locally required authorization must be obtained from the patient prior to performing any protocol-related procedures, including screening evaluations
  • At least 18 years of age
  • Up to three prior systemic therapy regimens for recurrent and/or metastatic disease. Prior exposure to PD-1/PD-L1 inhibitor monotherapy, prior exposure to CTLA-4 inhibitor monotherapy, or prior exposure to IRX-2 monotherapy is allowed.
  • Eastern Cooperative Oncology Group (ECOG) 0-2
  • Adequate normal organ and marrow function as outlined in protocol documentation
  • Must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as outlined in Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
  • Life expectancy of greater than 3 months.
  • Female participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to enrollment.
  • Body weight must be > 30 Kg.

Exclusion Criteria:

  • Prior exposure to a combination of PD-1/PD-L1 inhibitors and CTLA-4 inhibitors.
  • Prior exposure to a combination of IRX-2 regimen, PD-1/PD-L1 inhibitors and CTLA-4 inhibitors.
  • Radiation therapy with a curable intent within 30 days of first dose of study treatment is excluded. However, radiation therapy with a palliative intent is allowed to treat after 14 days from the last dose of radiation.
  • Any medical contraindications or previous therapy that would preclude treatment with the IRX-2 Regimen, durvalumab, or tremelimumab.
  • Any unresolved toxicity NCI Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria, and except toxicities the investigator deems irreversible.
  • Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician
  • Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with IRX-2, durvalumab or tremelimumab may be included only after consultation with the study physician.
  • Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion: Patients with vitiligo or alopecia; Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement. Any chronic skin condition that does not require systemic therapy; Patients without active disease in the last 2 years may be included but only after consultation with the study physician; Patients with celiac disease controlled by diet alone.
  • Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion: Intranasal, inhaled, topical steroid, or local steroid injections (e.g., intra articular injection); Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent; Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
  • Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of durvalumab and tremelimumab. Note: Local surgery of isolated lesions for palliative intent is acceptable.
  • History of allogenic organ transplantation.
  • Symptomatic cardiopulmonary disease (including congestive heart failure and hypertension), coronary artery disease, serious arrhythmia or chronic lung disease. Patients with these conditions who are stable with relatively minor symptoms and who are appropriate candidates for systemic treatments need not be excluded.
  • Myocardial infarction within the last 3 months.
  • Known infection with hepatitis B, hepatitis C, or HIV.
  • Signs or symptoms of systemic bacterial infection (use of antibiotics to treat superficial infection or contamination of tumor shall not, by itself, be considered evidence of infection).
  • Clinically significant gastritis or peptic ulcer disease.
  • Stroke or other symptoms of cerebral vascular insufficiency within the last 3 months.
  • Allergy to ciprofloxacin (or other quinolones).
  • Previous diagnosis of invasive cancer from which the individual is not disease-free AND that has required treatment within the past 3 years, except for superficial skin, cervical cancer in-situ, or early stage prostate or bladder cancer (i.e. treatment with curative intent and long term disease-free expectations).
  • History of leptomeningeal carcinomatosis
  • Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
  • Females who are pregnant or breastfeeding; males or females of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy or 1 year after last dose of cyclophosphamide, whichever is the longer time period.
  • Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
  • Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart).
  • History of active primary immunodeficiency
  • Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis (TB) testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  • Receipt of live attenuated vaccine within 30 days prior to the first dose of investigational produce (IP). Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03381183


Locations
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute Not yet recruiting
Tampa, Florida, United States, 33612
Contact: Brian Trank    813-745-5269    brian.trank@moffitt.org   
Contact: Christine Chung, M.D.    813-745-5431    christine.chung@moffitt.org   
Principal Investigator: Christine Chung, M.D.         
United States, Georgia
Emory University School of Medicine Not yet recruiting
Atlanta, Georgia, United States, 30322
Contact: Nabil Saba, M.D.    404-778-3126    nfsaba@emory.edu   
Principal Investigator: Nabil Saba, M.D.         
United States, Michigan
University of Michigan Health System Not yet recruiting
Ann Arbor, Michigan, United States, 48019
Contact: Paul Swiecicki, M.D.    248-613-5992    pswiecic@med.umich.edu   
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
Investigators
Principal Investigator: Christine Chung, M.D. H. Lee Moffitt Cancer Center and Research Institute

Additional Information:
Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier: NCT03381183     History of Changes
Other Study ID Numbers: MCC-19356
ESR-16-12571 ( Other Identifier: AstraZeneca )
First Posted: December 21, 2017    Key Record Dates
Last Update Posted: March 29, 2018
Last Verified: March 2018

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

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Squamous Cell
Head and Neck Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Neoplasms by Site
Antibodies, Monoclonal
Tremelimumab
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents