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Pembrolizumab Plus Olaparib in LA-HNSCC

Primary Purpose

Squamous Cell Carcinoma of Head and Neck

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Pembrolizumab
Olaparib
Cisplatin
IMRT (intensity modulated radiation therapy)
Sponsored by
UNC Lineberger Comprehensive Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Squamous Cell Carcinoma of Head and Neck focused on measuring head and neck, squamous cell carcinoma, HPV negative, pembrolizumab, olaparib, PARP inhibitor, anti-PD1 inhibitor, intensity modulation radiation therapy, Proton therapy, cisplatin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

In order to participate in this study, a subject must meet all of the eligibility criteria outlined below.

  1. Age >18 years on the day of signing the consent
  2. Written informed consent obtained to participate in the study and HIPAA authorization for release of personal health information.
  3. Subject is willing and able to comply with study procedures based on the judgment of the investigator or protocol designee. The subject must be willing to consent to a mandatory pre-study biopsy unless sufficient archival tissue is available.
  4. Biopsy confirmed American Joint Committee on Cancer 8th Edition35 stage III-IV B oral cavity squamous cell carcinoma (SCC), p16-negative oropharyngeal SCC, stage III-IVB hypopharyngeal SCC, stage III-IVB laryngeal SCC -OR- HPV-associated oropharyngeal SCC (p16 positive or HPV-associated) T4 or N3 , T1-3 N2 or T3N0-1 with >10 pack-year tobacco history
  5. At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by imaging (CT/ PET) and is suitable for repeated assessment.
  6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  7. No prior curative attempts for this cancer (i.e., surgery, radiation, systemic therapy) and not currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of the study intervention. No evidence of metastatic disease (M0)

Exclusion Criteria

  1. Subjects with prior and concurrent malignancies of different tumor types whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the study drug are eligible with the following exception: Subjects with prior history of HNSCC treated < 3 years to the date of consent.
  2. Cisplatin-ineligible as defined in the protocol.
  3. Severe, active medical comorbidity. Subjects are considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography scan or any psychiatric disorder that prohibits obtaining informed consent.
  4. Subjects unable to swallow orally administered medication prior to initiation of study treatment.
  5. Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of clinical interest of suspected immunologic etiology

Sites / Locations

  • UNC LinebergerRecruiting
  • Medical University of South Carolina (MUSC)Recruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Single Arm

Arm Description

The participants will receive neoadjuvant and adjuvant pembrolizumab and olaparib combination plus standard of care (chemoradiation therapy) as defined in the protocol.

Outcomes

Primary Outcome Measures

One Year Progression Free Survival (PFS)
One Year PFS will be defined as the period from the date of treatment start until disease progression or death (whichever occurs first) up to one year. Subjects who have not had an event will be censored at the date of last disease assessment documenting the subject was free of progression. Progression will be evaluated by RECIST v1.1 RECIST v.1.1: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Secondary Outcome Measures

Overall survival
Overall survival will be defined as the period from the date of treatment start until death of any cause. Subjects who have not had an event will be censored at the date of last assessment documenting the subject was alive.
Two Year Progression Free Survival (PFS)
Two Year PFS will be defined as the period from the date of treatment start until disease progression or death (whichever occurs first) up to two year. Subjects who have not had an event will be censored at the date of last disease assessment documenting the subject was free of progression. Progression will be evaluated by RECIST v1.1 RECIST v.1.1: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Induction therapy related delays in chemoradiation therapy
Induction therapy related delays in chemoradiation therapy (CRT) will be defined type and associated grade of toxicity according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0. criteria and days of delay to start CRT due to induction one cycle of induction pembrolizumab and olaparib.
Toxicities related to maintenance therapy
Toxicities related to maintenance therapy associated with pembrolizumab and olaparib will be classified and graded according to NCI-CTCAE v5.0. The NCI Common Terminology Criteria for Adverse Events is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.
Induction related toxicity using patient-reported outcomes
Induction pembrolizumab and olaparib related toxicity will be defined using Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) in subjects receiving one cycle of pembrolizumab and olaparib.
Patient reported maintenance therapy-related toxicities
Maintenance therapy-related toxicities using patient-reported outcomes (PRO-CTCAE) in subjects who received induction pembrolizumab with olaparib, followed by definitive treatment with concurrent cisplatin-radiotherapy and maintenance pembrolizumab and olaparib.
One-year locoregional control
One-year locoregional control will be defined as the period from the start of treatment until recurrence at primary site or nodal site (whichever occurs first) as defined by RECIST 1.1
Distant Metastasis-Free Survival (DMFS)
DMFS will be defined as the period from the date of treatment start until distant metastasis or death (whichever occurs first) as defined by RECIST 1.1. Subjects who have not had an event will be censored at the date of last disease assessment documenting the subject was free of distant metastasis.
Correlate Combined Positive Score (CPS) and one-year progression free survival (PFS)
To correlate combined positive score (CPS) with one-year PFS, quality of life scores will be summarized using descriptive statistics like mean, sd, median, range, in participants who received induction pembrolizumab with olaparib, followed by definitive treatment with concurrent cisplatin-radiotherapy and maintenance pembrolizumab and olaparib.
Head and Neck Cancer Associated Patient Reported Outcomes (PRO)
Head and Neck Cancer Associated PRO will be evaluated using European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Head and Neck Module (QLQ-H&N35). EORTC QLQ-H&N35 has 35 questions assessing symptoms and side effects of treatment, social function and body image/sexuality. Most questions used 4 point scale (1 'Not at all' to 4 'Very much'); several single item questions were just coded as no=1, yes=2. The scores transformed and analyzed on a 0 - 100 scale. High scores indicate more problems.
General Cancer Associated Patient Reported Outcomes (PRO)
General Cancer Associated PRO will be evaluated using European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). The EORTC QLQ-C30 has 30 questions, 9 multi-items: 5 functional, 9 symptoms and a global health and quality-of-life. Most questions used 4-point scale (1 'Not at all' to 4 'Very much'); 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). The scores transformed and analyzed on a 0 - 100 scale. A higher score=better.

Full Information

First Posted
May 4, 2022
Last Updated
September 20, 2023
Sponsor
UNC Lineberger Comprehensive Cancer Center
Collaborators
Merck Sharp & Dohme LLC
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1. Study Identification

Unique Protocol Identification Number
NCT05366166
Brief Title
Pembrolizumab Plus Olaparib in LA-HNSCC
Official Title
A Phase II Trial of Induction and Maintenance Pembrolizumab and Olaparib in Locally Advanced Head and Neck Squamous Cell Carcinoma (HNSCC)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 2, 2022 (Actual)
Primary Completion Date
October 31, 2024 (Anticipated)
Study Completion Date
October 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
UNC Lineberger Comprehensive Cancer Center
Collaborators
Merck Sharp & Dohme LLC

4. Oversight

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.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this research study is to evaluate the effectiveness of using a combination of pembrolizumab and olaparib when given before and after standard chemoradiation therapy in treating locally advanced head and neck squamous cell carcinoma. Pembrolizumab and olaparib are drugs that are approved for head and neck cancer treatment. However, FDA has not approved the use of these two drugs together in treating head and neck cancer.
Detailed Description
Treatment outcomes are poor for patients with locally advance human papilloma virus (HPV) negative and high-risk HPV positive head and neck squamous cell carcinoma (HNSCC). One standard of care (SOC) for HNSCC is definitive chemoradiotherapy (CRT). This study will evaluate the safety and efficacy of the addition of pembrolizumab, an anti-programmed death-1 (PD1) inhibitor, and olaparib, a Polyadenosine 5'diphosphoribose polymerization (PARP) inhibitor, before and after SOC CRT, which will be delivered in 70 Gray in 35 fractions with concurrent weekly cisplatin 40 mg/m2 over 7 weeks. Treatment will be offered in three sequential phases. In the induction phase, participants will receive one infusion of pembrolizumab and will take olaparib tablets for a total of 21 days. In the chemoradiation phase, radiation therapy will administered daily (excluding weekends) and cisplatin infusion will be given weekly. In the maintenance phase, pembrolizumab infusion will be done once every 6 weeks in additional to twice daily olaparib tablets for up to 8 treatment cycles that are 42-days per cycle.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Squamous Cell Carcinoma of Head and Neck
Keywords
head and neck, squamous cell carcinoma, HPV negative, pembrolizumab, olaparib, PARP inhibitor, anti-PD1 inhibitor, intensity modulation radiation therapy, Proton therapy, cisplatin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
45 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Single Arm
Arm Type
Experimental
Arm Description
The participants will receive neoadjuvant and adjuvant pembrolizumab and olaparib combination plus standard of care (chemoradiation therapy) as defined in the protocol.
Intervention Type
Biological
Intervention Name(s)
Pembrolizumab
Other Intervention Name(s)
KEYTRUDA®, MK-3475
Intervention Description
In the induction phase, participants will receive a single intravenous infusion of pembrolizumab 400 mg prior to chemoradiotherapy. In the Maintenance Phase, participants will receive pembrolizumab 400 mg every 42 days for 8 cycles.
Intervention Type
Drug
Intervention Name(s)
Olaparib
Other Intervention Name(s)
AZD-2281, MK-7339, KU0059436
Intervention Description
In the induction phase, participants will receive daily oral olaparib 150 mg two times a day for 3 weeks prior to chemoradiotherapy. In the Maintenance Phase, participants will receive daily olaparib 150 mg two times a day for up to 48 weeks.
Intervention Type
Drug
Intervention Name(s)
Cisplatin
Other Intervention Name(s)
CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-platinum
Intervention Description
In the chemoradiation phase, participants will receive weekly intravenous cisplatin infusion, 40 mg/m2 over 7 weeks. In the chemoradiation phase, standard of care radiation therapy and chemotherapy will be administered, for a total of 7 weeks. Radiation therapy is done on daily basis (excluding weekends), and chemotherapy therapy will involve cisplatin infusion once weekly.
Intervention Type
Radiation
Intervention Name(s)
IMRT (intensity modulated radiation therapy)
Intervention Description
In the chemoradiation phase, participants will receive 70 Gray external beam radiotherapy, at 2 Gray/fraction dose, 35 fractions, delivered once a day, on weekdays, using Intensity Modulated Radiotherapy Treatments or proton radiotherapy techniques, over 7 weeks.
Primary Outcome Measure Information:
Title
One Year Progression Free Survival (PFS)
Description
One Year PFS will be defined as the period from the date of treatment start until disease progression or death (whichever occurs first) up to one year. Subjects who have not had an event will be censored at the date of last disease assessment documenting the subject was free of progression. Progression will be evaluated by RECIST v1.1 RECIST v.1.1: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame
up to 1 year from start of treatment
Secondary Outcome Measure Information:
Title
Overall survival
Description
Overall survival will be defined as the period from the date of treatment start until death of any cause. Subjects who have not had an event will be censored at the date of last assessment documenting the subject was alive.
Time Frame
up to 2 years from start of treatment
Title
Two Year Progression Free Survival (PFS)
Description
Two Year PFS will be defined as the period from the date of treatment start until disease progression or death (whichever occurs first) up to two year. Subjects who have not had an event will be censored at the date of last disease assessment documenting the subject was free of progression. Progression will be evaluated by RECIST v1.1 RECIST v.1.1: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame
Up to 2 years from start of treatment
Title
Induction therapy related delays in chemoradiation therapy
Description
Induction therapy related delays in chemoradiation therapy (CRT) will be defined type and associated grade of toxicity according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0. criteria and days of delay to start CRT due to induction one cycle of induction pembrolizumab and olaparib.
Time Frame
Up to 14 weeks from start of treatment
Title
Toxicities related to maintenance therapy
Description
Toxicities related to maintenance therapy associated with pembrolizumab and olaparib will be classified and graded according to NCI-CTCAE v5.0. The NCI Common Terminology Criteria for Adverse Events is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.
Time Frame
Up to 2 years from start of treatment
Title
Induction related toxicity using patient-reported outcomes
Description
Induction pembrolizumab and olaparib related toxicity will be defined using Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) in subjects receiving one cycle of pembrolizumab and olaparib.
Time Frame
Up to 2 years from start of treatment
Title
Patient reported maintenance therapy-related toxicities
Description
Maintenance therapy-related toxicities using patient-reported outcomes (PRO-CTCAE) in subjects who received induction pembrolizumab with olaparib, followed by definitive treatment with concurrent cisplatin-radiotherapy and maintenance pembrolizumab and olaparib.
Time Frame
Up to 2 years from start of treatment
Title
One-year locoregional control
Description
One-year locoregional control will be defined as the period from the start of treatment until recurrence at primary site or nodal site (whichever occurs first) as defined by RECIST 1.1
Time Frame
Up to 1 year from start of treatment
Title
Distant Metastasis-Free Survival (DMFS)
Description
DMFS will be defined as the period from the date of treatment start until distant metastasis or death (whichever occurs first) as defined by RECIST 1.1. Subjects who have not had an event will be censored at the date of last disease assessment documenting the subject was free of distant metastasis.
Time Frame
Up to 1 year from start of treatment
Title
Correlate Combined Positive Score (CPS) and one-year progression free survival (PFS)
Description
To correlate combined positive score (CPS) with one-year PFS, quality of life scores will be summarized using descriptive statistics like mean, sd, median, range, in participants who received induction pembrolizumab with olaparib, followed by definitive treatment with concurrent cisplatin-radiotherapy and maintenance pembrolizumab and olaparib.
Time Frame
Up to 1 year
Title
Head and Neck Cancer Associated Patient Reported Outcomes (PRO)
Description
Head and Neck Cancer Associated PRO will be evaluated using European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Head and Neck Module (QLQ-H&N35). EORTC QLQ-H&N35 has 35 questions assessing symptoms and side effects of treatment, social function and body image/sexuality. Most questions used 4 point scale (1 'Not at all' to 4 'Very much'); several single item questions were just coded as no=1, yes=2. The scores transformed and analyzed on a 0 - 100 scale. High scores indicate more problems.
Time Frame
Baseline, 4week, 7 week, 12 weeks, 6months, 12 months, 18 months, 24 months, 36 months, 48 months, 60 months
Title
General Cancer Associated Patient Reported Outcomes (PRO)
Description
General Cancer Associated PRO will be evaluated using European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). The EORTC QLQ-C30 has 30 questions, 9 multi-items: 5 functional, 9 symptoms and a global health and quality-of-life. Most questions used 4-point scale (1 'Not at all' to 4 'Very much'); 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). The scores transformed and analyzed on a 0 - 100 scale. A higher score=better.
Time Frame
Baseline, 4week, 7week, 12 weeks, 6 months, 12 months, 18 months, 24 months, 36 months, 48 months, 60 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: In order to participate in this study, a subject must meet all of the eligibility criteria outlined below. Age >18 years on the day of signing the consent Written informed consent obtained to participate in the study and HIPAA authorization for release of personal health information. Subject is willing and able to comply with study procedures based on the judgment of the investigator or protocol designee. The subject must be willing to consent to a mandatory pre-study biopsy unless sufficient archival tissue is available. Biopsy confirmed American Joint Committee on Cancer 8th Edition35 stage III-IV B oral cavity squamous cell carcinoma (SCC), p16-negative oropharyngeal SCC, stage III-IVB hypopharyngeal SCC, stage III-IVB laryngeal SCC -OR- HPV-associated oropharyngeal SCC (p16 positive or HPV-associated) T4 or N3 , T1-3 N2 or T3N0-1 with >10 pack-year tobacco history At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by imaging (CT/ PET) and is suitable for repeated assessment. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 No prior curative attempts for this cancer (i.e., surgery, radiation, systemic therapy) and not currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of the study intervention. No evidence of metastatic disease (M0) Exclusion Criteria Subjects with prior and concurrent malignancies of different tumor types whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the study drug are eligible with the following exception: Subjects with prior history of HNSCC treated < 3 years to the date of consent. Cisplatin-ineligible as defined in the protocol. Severe, active medical comorbidity. Subjects are considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography scan or any psychiatric disorder that prohibits obtaining informed consent. Subjects unable to swallow orally administered medication prior to initiation of study treatment. Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of clinical interest of suspected immunologic etiology
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Lori Stravers
Phone
919-966-8535
Email
lori_stravers@med.unc.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Lynn Ruffin
Email
lynn_ruffin@med.unc.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Siddharth Sheth, DO MPH
Organizational Affiliation
UNC Lineberger Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
UNC Lineberger
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27514
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lori Stravers
Email
lori_stravers@med.unc.edu
Facility Name
Medical University of South Carolina (MUSC)
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Madison Avinger
Phone
843-792-4421
Email
avingerm@musc.edu
First Name & Middle Initial & Last Name & Degree
Kendall Preston
Phone
843-792-4421
Email
prestoke@musc.edu
First Name & Middle Initial & Last Name & Degree
John Kaczmar, MD

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
http://unclineberger.org/patientcare/clinical-trials/clinical-trials
Description
University of North Carolina Lineberger Comprehensive Cancer Center Clinical Trials

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Pembrolizumab Plus Olaparib in LA-HNSCC

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