Clinical trial NCT03655444: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Head and Neck Squamous Cell Carcinoma
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: Eli Lilly and Company
First posted: 2018-08-31
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Phase I Only: Determine the Recommended Phase 2 Dose of Abemaciclib Combined With a Fixed Dose of Nivolumab
timeFrame: Completion of enrollment to Phase I portion of study (estimated to be 3 months)
measure: Overall Survival (OS) Rate
timeFrame: Until death (estimated average of 13 months)
Secondary outcomes:
measure: Phase II Only: Best Overall Tumor Response
timeFrame: Through completion of treatment (estimated to be 5 months)
measure: Phase II Only: Duration of Tumor Response
timeFrame: Through completion of treatment (estimated to be 5 months)
measure: Progression-free Survival (PFS)
timeFrame: Through completion of treatment (estimated to be 5 months)
measure: Adverse Events (AEs) Associated With the Combination of Abemaciclib and Nivolumab.
timeFrame: Through 30 days after completion of treatment (estimated to be 6 months)
measure: Phase II Lead-In Only: Changes in Peripheral Blood Lymphocyte Subsets
timeFrame: Compare before and after one week of abemaciclib monotherapy
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Douglas R Adkins, M.D.
role: PRINCIPAL_INVESTIGATOR
References: