Abemaciclib + Nivolumab in Patients With Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma That Progressed or Recurred Within Six Months After Platinum-based Chemotherapy

• ClinicalTrials.gov Identifier: NCT03655444
• Recruitment Status: Terminated
• First Posted: August 31, 2018
• Results First Posted: December 3, 2020
• Last Update Posted: December 3, 2020
• Sponsor: Washington University School of Medicine
• Collaborator: Eli Lilly and Company
• Information provided by (Responsible Party): Washington University School of Medicine

Tracking Information

• First Submitted Date: August 30, 2018
• First Posted Date: August 31, 2018
• Results First Submitted Date: November 9, 2020
• Results First Posted Date: December 3, 2020
• Last Update Posted Date: December 3, 2020
• Actual Study Start Date: May 29, 2019
• Actual Primary Completion Date: August 24, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 9, 2020)

• Phase I Only: Determine the Recommended Phase 2 Dose of Abemaciclib Combined With a Fixed Dose of Nivolumab [ Time Frame: Completion of enrollment to Phase I portion of study (estimated to be 3 months) ]
  -The RP2D of abemaciclib is defined as the highest dose level at which fewer than 2 patients of a cohort of three patients experience a dose-limiting toxicity (DLT) during the first cycle.
• Overall Survival (OS) Rate [ Time Frame: Until death (estimated average of 13 months) ]
  • OS is defined as the time from the date of treatment to the date of death, censored at the last follow-up otherwise.
  • The mean survival time and standard error were underestimated because the largest observation was censored and the estimation was restricted to the largest event time.

Original Primary Outcome Measures (submitted: August 30, 2018)

• Phase I Only: Determine the Recommended Phase 2 Dose of Abemaciclib Combined With a Fixed Dose of Nivolumab [ Time Frame: Completion of enrollment to Phase I portion of study (estimated to be 3 months) ]
  -The RP2D of abemaciclib is defined as the highest dose level at which fewer than 2 patients of a cohort of three patients experience a dose-limiting toxicity (DLT) during the first cycle.
• Phase II only: Overall survival (OS) rate [ Time Frame: Until death (estimated average of 13 months) ]
  -OS is defined as the time from the date of treatment to the date of death, censored at the last follow-up otherwise.

Current Secondary Outcome Measures (submitted: November 9, 2020)

• Phase II Only: Best Overall Tumor Response [ Time Frame: Through completion of treatment (estimated to be 5 months) ]
  • Complete response: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm, Disappearance of all non-target lesions and normalization of tumor marker level.
  • Partial response: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.
• Phase II Only: Duration of Tumor Response [ Time Frame: Through completion of treatment (estimated to be 5 months) ]
  -The duration of overall response is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
• Progression-free Survival (PFS) [ Time Frame: Through completion of treatment (estimated to be 5 months) ]
  -PFS is defined as the time from treatment to the date of progression or death, whichever occurs first. The alive patients without progression is censored at the last follow-up.
• Adverse Events (AEs) Associated With the Combination of Abemaciclib and Nivolumab. [ Time Frame: Through 30 days after completion of treatment (estimated to be 6 months) ]
  -The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.
• Phase II Lead-In Only: Changes in Peripheral Blood Lymphocyte Subsets [ Time Frame: Compare before and after one week of abemaciclib monotherapy ]

Original Secondary Outcome Measures (submitted: August 30, 2018)

• Phase II only: Best tumor response [ Time Frame: Through completion of treatment (estimated to be 5 months) ]
  • Complete response: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm, Disappearance of all non-target lesions and normalization of tumor marker level.
  • Partial response: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.
• Phase II Only: Duration of Tumor Response [ Time Frame: Through completion of treatment (estimated to be 5 months) ]
  -The duration of overall response is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
• Phase II only: Progression-free survival (PFS) [ Time Frame: Through completion of treatment (estimated to be 5 months) ]
  -PFS is defined as the time from treatment to the date of progression or death, whichever occurs first. The alive patients without progression is censored at the last follow-up.
• Phase II only: Adverse events (AEs) associated with the combination of abemaciclib and nivolumab. [ Time Frame: Through 30 days after completion of treatment (estimated to be 6 months) ]
  -The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Abemaciclib + Nivolumab in Patients With Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma That Progressed or Recurred Within Six Months After Platinum-based Chemotherapy
• Official Title: A Prospective Phase I and II Trial of Abemaciclib + Nivolumab in Patients With Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma That Progressed or Recurred Within Six Months After Platinum-based Chemotherapy

Brief Summary

In phase I of the trial, the investigators aim to explore the safety and feasibility of abemaciclib in combination with nivolumab in patients with recurrent/metatstatic head and neck squamous cell carcinoma (RM-HNSCC). A dose de-escalation study design will be used to determine the recommended phase II dose (RP2D) of abemaciclib given with the standard dose of nivolumab.

In phase II of the trial, the investigators aim to determine if abemaciclib and nivolumab will improve the one year survival from 36% (historical comparison with nivolumab) to 60% (abemaciclib + nivolumab) in patients with RM-HNSCC that had progressed or recurred within six months after platinum-based chemotherapy. Patients will be treated with abemaciclib at the recommended phase 2 dose (RP2D) in combination with standard doses of nivolumab. If this aim is met, genome sequencing, bulk and single cell RNAseq, and selected protein expression and deep cellular phenotyping will be performed on tumor tissue and blood obtained before and during treatment with abemaciclib and nivolumab. These biomarker data will be correlated with survival and tumor response to abemaciclib and nivolumab.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Head and Neck Squamous Cell Carcinoma

Intervention

• Drug: Abemaciclib
  Abemaciclib is an investigational agent for this trial and will be supplied by Lilly Oncology, free of charge to the patient.
  Other Name: Verzenio
• Drug: Nivolumab
  Nivolumab is commercially available
  Other Name: Opdivo
• Procedure: Tumor biopsy
  • Phase II patients only
  • If the patient consents, fresh tumor tissue will be collected at baseline and then during Cycle 2 (between days 8-22) of abemaciclib and nivolumab.
• Procedure: Peripheral blood
  • Phase II patients only
  • Peripheral blood will be collected at baseline, at the end of the Lead In (cycle 1 day 1 prior to treatment), during cycle 2 (between days 8-22), and during cycle 3 (between days 21-28). If patient does not have progression after cycle 3, patient will also have peripheral blood collected at time of progression.
• Other: EORTC QLQ-30
  • Phase II patients only
  • Screening , Cycle 2 D1, Cycle 4 D1, and End of treatment (EOT)

Study Arms

• Experimental: Phase I: Abemaciclib + Nivolumab
  • Abemaciclib (150 mg) will be administered orally twice per day (with or without food) on Days 1 through 28 of every 4-week cycle
  • Nivolumab 480 mg will be given intravenously (IV) over 30 minutes on Day 1 of every 4-week cycle.
  Interventions:

  • Drug: Abemaciclib
  • Drug: Nivolumab
• Experimental: Phase II: Abemaciclib + Nivolumab
  • Phase II Lead-in: Patients will be treated with abemaciclib monotherapy at the recommended phase II dose (150 mg) on Day -7 through Day -1 prior to starting Cycle 1 with the combination of abemaciclib and nivolumab. Patients will proceed directly from Day -1 to Cycle 1 Day 1 of combination abemaciclib + nivolumab, there is not a Day 0.
  • Patients will be treated with abemaciclib at the RP2D (150 mg) (Days 1 through 28) + nivolumab (480 mg, Day 1) of each 4-week cycle.
  Interventions:

  • Drug: Abemaciclib
  • Drug: Nivolumab
  • Procedure: Tumor biopsy
  • Procedure: Peripheral blood
  • Other: EORTC QLQ-30

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: November 9, 2020): 6
• Original Estimated Enrollment (submitted: August 30, 2018): 32
• Actual Study Completion Date: August 24, 2020
• Actual Primary Completion Date: August 24, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Incurable RM-HNSCC, defined as disease not amenable to cure by surgery and/or radiation therapy (or patient declines or is ineligible for surgery and/or radiation therapy).

• Disease Evaluation:

  • Phase I: evaluable or measurable disease.
  • Phase II: 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, as ≥ 20 mm by chest x-ray, or ≥ 10 mm by clinical exam.

• Prior Treatment:

  • Phase I: any number of lines of prior therapy for RM-HNSCC.
  • Phase I: prior therapy with inhibitors of CDK4/6 or PD-L1/PD-1 is acceptable.
  • Phase II: RM-HNSCC that progressed or recurred within six months of platinum-based therapy (given for curable or incurable disease).
  • Phase II: prior therapy with inhibitors of CDK4/6 or PD-L1/PD-1 is not acceptable.
• 18 years of age or older
• Performance status 0-1 (ECOG)

• Adequate blood and organ function as defined:

  • Absolute neutrophil count ≥ 1,500/mcL
  • Platelets ≥ 100,000/mcL
  • Hemoglobin ≥ 8.0 g/dL
  • Total bilirubin ≤ 1.5 x ULN mg/dL
  • AST(SGOT) ≤ 3 x IULN and ALT(SGPT) ≤ 3 x IULN
  • Creatinine ≤ 2 x ULN OR creatinine clearance ≥ 40 mL/min/1.73 m2
  • INR ≤ 1.5 x ULN and PTT ≤ 1.5 x ULN (Patients are allowed to be on anticoagulation)
• Able to swallow oral medication
• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) beginning 14 days prior to first dose of abemaciclib, through the dosing period, and for at least 28 days after.
• Signed IRB approved written informed consent document.

Exclusion Criteria:

• Phase II: prior inhibitors of CDK4/6 or PD-L1/PD-1 for treatment of incurable HNSCC.
• Radiation within 14 days of treatment start (patients who received radiotherapy must have completed and fully recovered from the acute side effects of radiotherapy), chemotherapy, targeted or investigational therapy within 21 days of treatment start.
• History of other malignancy ≤ 1 year prior to consent with the exception of completely resected skin carcinoma or other cancers with a low risk of recurrence.
• Ongoing toxicity attributed to prior anti-cancer therapy that is > grade 1, except alopecia or peripheral neuropathy
• Active central nervous system metastases: defined as currently receiving radiation therapy to metastatic CNS disease. Once radiation therapy is completed, patients with CNS disease are eligible if they meet all other criteria for enrollment.
• History of severe allergic reactions attributed to agents used in the study.
• Serious uncontrolled inter-current illness within the 3 months prior to study entry or psychiatric illness/social situations that would limit compliance with study requirements.
• Serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (i.e., interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
• Active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]. Screening is not required for enrollment.
• History of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.
• Pregnant and/or breastfeeding. Patient must have a negative serum pregnancy test within 7 days of first dose of treatment.
• Active serious autoimmune disease requiring systemic immunosuppression (biologics, prednisone equivalent dose > 20 mg/day).
• Current use of strong CYP3A inhibitors or inducers.

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: NCT03655444
• Other Study ID Numbers: 201810019
• 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
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Washington University School of Medicine
• Study Sponsor: Washington University School of Medicine
• Collaborators: Eli Lilly and Company

Investigators

• Principal Investigator: Douglas R Adkins, M.D.; Washington University School of Medicine

• PRS Account: Washington University School of Medicine
• Verification Date: November 2020