Alisertib and Pembrolizumab for the Treatment of Patients With Rb-deficient Head and Neck Squamous Cell Cancer
- Conditions
- Head and Neck Squamous Cell CarcinomaMalignant Solid Neoplasm
- Interventions
- Registration Number
- NCT04555837
- Lead Sponsor
- M.D. Anderson Cancer Center
- Brief Summary
This phase I/II trial investigates the best dose and effect of alisertib in combination with pembrolizumab in treating patients with Rb-deficient head and neck squamous cell cancer. Alisertib may help block the growth of cancer.. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Giving alisertib in combination with pembrolizumab may help control Rb-deficient head and neck squamous cell cancer. HPV positive head and neck cancers are Rb-deficient.
- Detailed Description
PRIMARY OBJECTIVES:
I. To determine the recommend phase II dose of the combination of alisertib and pembrolizumab. (Phase I) II. To determine the overall response rate (ORR) and progression free survival (PFS) of patients with recurrent or metastatic Rb-deficient head and neck squamous cell carcinoma (HNSCC) treated with the combination of pembrolizumab and alisertib. (Phase II)
SECONDARY OBJECTIVES:
I. To evaluate the safety of the combination of pembrolizumab and alisertib in patients with solid tumors.
II. To determine the overall survival in HNSCC patients treated with the combination of pembrolizumab and alisertib.
III. To determine the relationship between pharmacokinetics, pharmacodynamics, baseline immune and tumor biomarkers and clinical responses in patients treated with alisertib and pembrolizumab.
IV. To determine correlations between clinical responses and the effect of the treatment on human papilloma virus (HPV)-reactive T cells in HPV+ cancers.
V. To determine correlations between clinical responses and tumor infiltrating lymphocyte function and T cell repertoire.
OUTLINE: This is a phase I, dose-escalation study of alisertib in combination with fixed dose pembrolizumab followed by a phase II study.
Patients receive alisertib orally (PO) twice daily (BID) on days 1-7 and pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 2-3 months.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 24
Not provided
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Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is considered to be over 25%.
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Prior allogeneic bone marrow or organ transplantation.
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Known gastrointestinal (GI) disease or GI procedures that could interfere with the oral absorption or tolerance of alisertib. Examples include, but are not limited to partial gastrectomy, history of small intestine surgery, and celiac disease.
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Inability to swallow (or use a feeding tube to administer) oral medication or inability or unwillingness to comply with the administration requirements related to alisertib.
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Known history of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease; requirement for supplemental oxygen.
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Requirement for constant administration of proton pump inhibitor, H2 antagonist, or pancreatic enzymes throughout the study. The intermittent use of H2-antagonists and antacids (including carafate) is only allowed within these guidelines:
- H2 antagonists until D-1 and after the dosing of alisertib is done
- Antacid formulations until 2 hours before doing and after 2 hours following dosing.
- PPI is allowed until D-5 of first alisertib dose. PPIs are prohibited throughout the study
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Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (see Section 7.3), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.
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Female subject who is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative urine or serum β-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.
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Female patient who intend to donate eggs (ova) during the course of this study or 120 days after receiving their last dose of study drug(s).
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Male patients who intend to donate sperm during the course of this study or 120 days after receiving their last dose of study drug(s).
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Other severe acute or chronic medical or psychiatric condition, including uncontrolled diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement for pancreatic enzymes, any condition that would modify small bowel absorption of oral medications, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for enrollment in this study.
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Diagnosed or treated for another invasive malignancy within 2 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
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Has received any anti-cancer treatment including investigational agents within 21 days prior to first dose of alisertib.
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Patients who receive gamma knife radiosurgery for brain metastases or whole brain radiation are eligible if gamma knife radiosurgery was completed > 2 weeks before treatment is started or whole brain radiation was performed > 4 weeks before treatment is started, and are clinically stable (not requiring steroids or anti-epileptic drugs).
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Known hypersensitivity to any of the excipients of alisertib enteric coated tablets or severe reaction to any human monoclonal antibody.
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Patients with a prior history of clinically significant metabolic acidosis (exclusion only for patients receiving alisertib oral solution).
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Major surgery within 28 days prior to first dose of alisertib or persisting side effects that have not improved to NCI-CTCAE grade 1 or better.
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Patients who are on (or will require) prolonged systemic corticosteroid treatment during the study except for replacement dosing for adrenal insufficiency.
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Concurrent severe and/or uncontrolled medical conditions that would, in the investigator's judgment, contraindicate patient participation in the clinical study or require concomitant anti-cancer drugs (e.g. active or uncontrolled severe infection, chronic active hepatitis, immuno-compromised, acute or chronic pancreatitis, uncontrolled high blood pressure, interstitial lung disease).
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Patients with active, known, diagnosed or suspected autoimmune disease. Patients suffering from vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring thyroid hormone replacement therapy, or psoriasis not requiring systemic treatment can be enrolled.
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Patients diagnosed with active interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis or another condition requiring immunosuppressive doses of systemic medication such as systemic corticosteroids or absorbed topical corticosteroids (doses ≥ 10 mg/day prednisone or equivalent) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical corticosteroids, adrenal replacement doses, or < 10 mg daily prednisone or equivalent are permitted.
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Administration of any live vaccine within 30 days before first dose of study drug.
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Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B virus or hepatitis C virus, except for: Patients with HIV who have controlled infection (undetectable viral load and CD4 count above 350 cells/mm3 either spontaneously or on a stable antiviral regimen) are permitted; Patients with hepatitis B (HepBsAg+) virus who have controlled infection (serum hepatitis B virus DNA PCR that is below the limit of detection AND receiving antiviral therapy for hepatitis B) are permitted; Patients who are hepatitis C virus antibody positive (HCV Ab +) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted.
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Participating in another therapeutic clinical trial.
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Prior immune-related adverse events (irAE) as follows:
A. Any life-threatening irAE will not be eligible.
B. Any grade irAE of the following types will not be eligible:
- i. Nervous system irAE
- ii. Ocular irAE
- iii. Cardiovascular irAE
- iv. Severe Cutaneous Adverse Reactions (SCAR)
- v. Hematological irAE
C. Any grade endocrine irAE will be eligible if replacement therapy can compensate for the resulting deficit.
D. Grade ≥ 2 irAE of the following will not be eligible:
- i. Colitis
- ii. Hepatitis
- iii. Bullous Dermatoses
- iv. Pneumonitis
- v. Musculoskeletal
- vi. Renal
E. Grade ≥ 3 cutaneous irAE will not be eligible.
F. All irAEs must have resolved to Grade ≤ 1 at least 14 days before the planned first dose.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Treatment (alisertib, pembrolizumab) Pembrolizumab Patients receive alisertib PO BID on days 1-7 and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Treatment (alisertib, pembrolizumab) Alisertib Patients receive alisertib PO BID on days 1-7 and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
- Primary Outcome Measures
Name Time Method Phase I: The Recommended Phase II Dose Determenation. Phase II: Overall Response Rate (ORR) and Progression Free Survival (PFS) Approximately 33 months Phase I: To determine the recommend phase II dose of the combination of alisertib and pembrolizumab
Phase II: Overall Response Rate (ORR) Approximately 33 months Phase II: To determine the overall response rate (ORR) of patients with recurrent or metastatic Rb-deficient head and neck squamous cell carcinoma (HNSCC) treated with the combination of pembrolizumab and alisertib.
Phase II: Progression Free Survival (PFS) Approximately 33 months Phase II: To determine the progression free survival (PFS) of patients with recurrent or metastatic Rb-deficient head and neck squamous cell carcinoma (HNSCC) treated with the combination of pembrolizumab and alisertib.
- Secondary Outcome Measures
Name Time Method The Safety of the Combination of Pembrolizumab and Alisertib Adverse events were monitored until off study due to disease progression, death, unacceptable toxicity, consent withdrawal, or physician's discretion, approximately 33 months. To evaluate the safety of the combination of pembrolizumab and alisertib in patients with solid tumors.
The Overall Survival in HNSCC Patients 28 patients (4 patients were screen failures) enrolled from September 2020 to June 2023, 24 were treated and evaluable for response. Patients were followed for overall survial for approximately 33 months To determine the overall survival in HNSCC patients treated with the combination of pembrolizumab and alisertib in Phase II only.
The Relationship Between Pharmacokinetics, Pharmacodynamics, Baseline Immune and Tumor Biomarkers and Clinical Responses The trial design dictated that if there were no objective responses in thefirst cohort of the phase II study, the trial would close after the first cohort. To determine the relationship between pharmacokinetics, pharmacodynamics, baseline immune and tumor biomarkers and clinical responses in patients treated with alisertib and pembrolizumab in phase II only.
Correlations Between Clinical Responses and the Effect of the Treatment on Human Papilloma Virus (HPV)-Reactive T Cells in HPV+ Cancers. The trial design dictated that if there were no objective responses in the first cohort of the phase II study, the trial would close after the first cohort. To determine correlations between clinical responses and the effect of the treatment on human papilloma virus (HPV)-reactive T cells in HPV+ cancers in phase II only.
Correlations Between Clinical Responses and Tumor Infiltrating Lymphocyte Function and T Cell Repertoire. The trial design dictated that if there were no objective responses in the first cohort of the phase II study, the trial would close after the first cohort. To determine correlations between clinical responses and tumor infiltrating lymphocyte function and T cell repertoire in phase II only.
Trial Locations
- Locations (1)
M D Anderson Cancer Center
🇺🇸Houston, Texas, United States