Study Of Dacomitinib (PF-00299804) In Advanced NSCLC Patients (Post Chemo Or Select First Line) To Evaluate Prophylactic Intervention On Derm And GI AEs And PRO

Study Overview
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Brief Summary
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To assess the impact of prophylactic treatment on the incidence of adverse events in advanced NSCLC patients (post chemotherapy) treated with dacomitinib daily as a single agent. To assess the impact of an interrupted dacomitinib dosing schedule in Cycle 1 on the incidence of adverse events in first-line advanced NSCLC patients with an EGFR mutation (HER-1 mutation, HER-2 mutation or HER-2 amplification).

Official Title
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ARCHER 1042: A PHASE 2 STUDY OF DACOMITINIB IN ADVANCED NON-SMALL CELL LUNG CANCER (POST-CHEMOTHERAPY OR SELECT FIRST LINE PATIENTS) TO EVALUATE PROPHYLACTIC INTERVENTION ON DERMATOLOGIC AND GASTROINTESTINAL ADVERSE EVENTS AND PATIENT REPORTED OUTCOMES

Conditions
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Non Small Cell Lung Cancer (NSCLC)

Intervention / Treatment
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* Drug: Dacomitinib
* Drug: Dacomitinib
* Drug: Doxycycline
* Drug: Probiotic
* Drug: Alclometasone cream


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Advanced Non-Small Cell Lung Cancer (NSCLC). For Cohort I and Cohort II, advanced NSCLC patients must have received at least one prior regimen of systemic therapy which includes at least one standard chemotherapy for advanced NSCLC and who have failed (ie, progressed or intolerant due to toxicity which precludes further treatment) standard therapy for advanced or metastatic disease. To be considered intolerant to treatment, a patient must have received at least two cycles to be considered previously treated. For Cohort III, advanced NSCLC patients must not have received prior systemic treatment for their advanced disease and require a known EGFR (HER-1) mutation, HER-2 mutation or HER-2 amplification. Cohort III patients could have received prior adjuvant chemotherapy for Stage I-III disease or combined modality chemotherapy-radiation for Stage IIIA disease is allowed if treatment completed>12 months prior to enrollment. All cohorts, patients must have evidence of disease; however, measurable disease is not required to enroll. Eastern Cooperative Oncology Group (ECOG) Performance status 0-2 Estimated creatinine clearance ≥15 mL/min. Exclusion Criteria: Prior treatment with an EGFR-targeted or HER-targeted agent (all cohorts). Chemotherapy, radiotherapy, biological or investigational agents within 2 weeks of baseline disease assessments (all cohorts). Patients with known diffuse interstitial lung disease (all cohorts). Investigational therapy as only treatment for advanced NSCLC without administration of an approved chemotherapy for advanced NSCLC (for Cohort I and Cohort II)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort I<br>Arm A: Dacomitinib 45 mg orally daily on a continuous schedule until disease progression, toxicity, death or withdrawal of consent Doxycycline placebo orally BID for 4 weeks Arm B: Dacomitinib 45 mg orally daily on a continuous schedule until disease progression, toxicity, death or withdrawal of consent Doxycycline 100 mg orally BID for 4 weeks | Drug: Dacomitinib<br>* Dacomitinib 45 mg orally daily on a continuous schedule until disease progression, toxicity, death or withdrawal of consent<br>Drug: Doxycycline<br>* Doxycycline or Doxycycline placebo BID for 4 weeks<br>|
| Experimental: Cohort II<br>Dacomitinib 45 mg orally daily on a continuous schedule until disease progression, toxicity, death or withdrawal of consent Topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks VSL#3 probiotic 4 capsules orally daily or 1 sachet orally daily for up to 5 weeks (starting between Day minus 7 to Day minus 4 and continuing through Day 28) | Drug: Dacomitinib<br>* Dacomitinib 45 mg orally daily on a continuous schedule until disease progression, toxicity, death or withdrawal of consent<br>Drug: Probiotic<br>* VSL#3 probiotic 4 capsules orally daily or 1 sachet orally daily for up to 5 weeks (starting between Day minus 7 to Day minus 4 and continuing through Day 28)<br>Drug: Alclometasone cream<br>* Topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks<br>|
| Experimental: Cohort III<br>Cohort III is an interrupted dosing schedule of dacomitinib in the first cycle only | Drug: Dacomitinib<br>* Dacomitinib 45 mg orally daily on a continuous schedule for the first 10 days in Cycle 1, followed by 4 days off treatment, followed by continuous daily dosing until disease progression, toxicity, death or withdrawal of consent<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Select Dermatologic Adverse Events of Interest (SDAEI) (All Causality, All Grade) in the First 8 Weeks of Treatment by Treatment Arm for Cohort I | SDAEI of all causality and all grades were evaluated in participants in Cohort I. These SDAEIs included dermatitis acneiform, dry skin, exfoliative rash, nail discoloration, nail disorder, paronychia, pruritus, rash, skin exfoliation, skin fissures, skin infection, skin laceration and skin ulcer. 95% confidence interval (CI) calculated using exact method based on binomial distribution. After protocol amendment 1, Arm C was removed from Cohort I and enrollment to Arm C was terminated. Only 7 participants were enrolled in Cohort I Arm C as a result. Given the smaller sample size, analyse of Outcome Measure 1 was not conducted in Cohort I Arm C. | First 8 Weeks of Treatment | 
| Percentage of Participants With SDAEI (All Causality, Grade Greater Than or Equal to [≥] 2) in the First 8 Weeks of Treatment by Treatment Arm for Cohort I | SDAEI of all causality and Grade ≥2 were evaluated in participants in Cohort I. These SDAEIs included dermatitis acneiform, dry skin, exfoliative rash, nail discoloration, nail disorder, paronychia, pruritus, rash, skin exfoliation, skin fissures, skin infection, skin laceration and skin ulcer. Adverse events (AEs) were graded for severity using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 4.0). 95% CI calculated using exact method based on binomial distribution. After protocol amendment 1, Arm C was removed from Cohort I and enrollment to Arm C was terminated. Only 7 participants were enrolled in Cohort I Arm C as a result. Given the smaller sample size, analyse of Outcome Measure 2 was not conducted in Cohort I Arm C. | First 8 Weeks of Treatment | 
| Mean Change From Baseline (Cycle 1 Day 1) Skindex-16 Scale Scores (Total Score, Symptoms Score, Emotion Score, and Functioning Score) by Treatment Arm for Cohort I | Patient Reported Outcomes (PROs) of Health Related Quality of Life (HRQoL) & disease/treatment-related symptoms were assessed using Dermatologic Survey (Skindex-16) that assesses bother. It includes 3 multi-item scales: symptoms, emotions & functioning. Individual scaled scores & total scores were determined. Skindex questions were transformed to a linear scale of 0 (never bothered) to 100 (always bothered). Subscale scores are an average of non-missing questions in a given scale if greater than (>) 75% of total subscale questions are non-missing. The Total Score is an average of all non-missing questions in the Skindex if >75% of total questions are non-missing. A negative change score represents a better quality of life. A change score of 10 points is considered clinically significant. Skindex completion criteria were defined as completion of 3 out of 4 items for questions 1 to 4, 6 out of 7 items for questions 5 to 11, 4 out of 5 items for questions 12 to 16 for the visit. | First 8 Weeks of Treatment | 
| Percentage of Participants With Diarrhea AEs (All Causality, All Grade and Grade ≥2) in the First 8 Weeks of Treatment for Cohort II | Diarrhea AEs of all causality, all grade and Grade ≥2 were evaluated in participants in Cohort II. AEs were graded for severity using the NCI-CTCAE, Version 4.0. 95% CI calculated using exact method based on binomial distribution. | First 8 Weeks of Treatment | 
| Mean Change From Baseline (Cycle 1 Day 1) Modified Oral Mucositis Daily Questionnaire (OMDQ) Scores (Mouth and Throat Soreness Categories and Scale, and Diarrhea Categories and Scale) for Cohort II | Diarrhea severity was assessed using the modified-OMDQ. This questionnaire is comprised of 6 questions in total; however, only two items relate to diarrhea symptoms (item 5 and item 6). Symptoms scores were developed for both the full questionnaire and for the diarrhea-only questions for each completed survey. Mucositis questions were transformed to a score range of 0 to 10. Increasing OMDQ values are associated with greater symptom burden. Modified OMDQ completion criteria were defined as completion of all 4 questions (questions 2, 4, 5 and 6). M/T = mouth and throat. | Cycles 1, 2, 3, 4, 5, and 6, EoT and Follow-up | 
| Percentage of Participants With SDAEI (All Causality, All Grade) in the First 8 Weeks of Treatment for Cohort II | SDAEI of all causality and all grades were evaluated in participants in Cohort II. These SDAEIs included dermatitis acneiform, dry skin, exfoliative rash, nail discoloration, nail disorder, paronychia, pruritus, rash, skin exfoliation, skin fissures, skin infection, skin laceration and skin ulcer. 95% CI calculated using exact method based on binomial distribution. | First 8 Weeks of Treatment | 
| Percentage of Participants With SDAEI (All Causality, Grade ≥2) in the First 8 Weeks of Treatment for Cohort II | SDAEI of all causality and Grade ≥2 were evaluated in participants in Cohort II. These SDAEIs included dermatitis acneiform, dry skin, exfoliative rash, nail discoloration, nail disorder, paronychia, pruritus, rash, skin exfoliation, skin fissures, skin infection, skin laceration and skin ulcer. AEs were graded for severity using the NCI-CTCAE, Version 4.0. 95% CI calculated using exact method based on binomial distribution. | First 8 Weeks of Treatment | 
| Mean Change From Baseline (Cycle 1 Day 1) Skindex-16 Scale Scores (Total Score, Symptoms Score, Emotion Score, and Functioning Score) for Cohort II | PROs of HRQoL and disease/treatment-related symptoms were assessed using Dermatologic Survey (Skindex-16) that assesses bother. It includes 3 multi-item scales: symptoms, emotions & functioning. Individual scaled scores & total scores were determined. Skindex questions were transformed to a linear scale of 0 (never bothered) to 100 (always bothered). Subscale scores are an average of non-missing questions in a given scale if > 75% of total subscale questions are non-missing. The Total Score is an average of all non-missing questions in the Skindex if >75% of total questions are non-missing. A negative change score represents a better quality of life. A change score of 10 points is considered clinically significant. Skindex completion criteria were defined as completion of 3 out of 4 items for questions 1 to 4, 6 out of 7 items for questions 5 to 11, 4 out of 5 items for questions 12 to 16 for the visit. | Cycles 1, 2, 3, 4, 5, and 6, EoT and Follow-up | 
| Mean Area Under the Plasma Concentration Time Curve From 0 to 24 Hours (AUC0-24) and From 0 to 120 Hours (AUC0-120) for Dacomitinib and Its Metabolite PF-05199265 on Cycle 1 Days 10 to 15 for Cohort III | AUC0-24 is the area under the plasma concentration-time curve (AUC) from time 0 to 24 hours post-dose. AUC0-120 is the AUC from time 0 to 120 hours post-dose. AUC was calculated by the linear trapezoidal method using a non-compartmental pharmacokinetic (PK) analysis. ng*hr/mL = nanogram hours per milliliter | Cycle 1 Day 10: Pre-dose and 2, 4, 6, 24, 48, 72, 96, and 120 hours post-dose (the 120 hour sample was obtained on Day 15 pre-dose). | 
| Mean Maximum Observed Plasma Concentrations (Cmax) for Dacomitinib and Its Metabolite PF-05199265 on Cycle 1 Days 10 to 15 for Cohort III | Cmax was obtained from direct inspection of the data. ng/mL = nanograms per milliliter | Cycle 1 Day 10: Pre-dose and 2, 4, 6, 24, 48, 72, 96, and 120 hours post-dose (the 120 hour sample was obtained on Day 15 pre-dose). | 
| Median Time of Occurrence of Cmax (Tmax) for Dacomitinib and Its Metabolite PF-05199265 on Cycle 1 Days 10 to 15 for Cohort III | Tmax was obtained from direct inspection of the data as the time of first occurence of Cmax. | Cycle 1 Day 10: Pre-dose and 2, 4, 6, 24, 48, 72, 96, and 120 hours post-dose (the 120 hour sample was obtained on Day 15 pre-dose). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Receiving Any Concomitant Drug or Non-Drug Treatment for SDAEI, Diarrhea and Mucositis for Cohort I by Treatment Arm, Cohort II, and Cohort III | Medications used concomitantly for SDAEIs, diarrhea and mucositis were evaluated for all participants who received dacomitinib on a continuous basis with a preemptive prophylactic (Cohorts I and II) or as an interrupted dosing regimen (Cohort III). | Screening to the Post-Teatment Follow-Up Visit (at least 28 days and no more than 35 days after the end of dacomitinib treatment due to progression of disease, intolerance to dacomitinib treatment, or participant withdrawal) | 
| Mean AUC From 0 to the End of the Dosing Interval (AUC0-tau) for Dacomitinib and Its Metabolite PF-05199265 on Cycle 2 Day 1 for Cohort I | AUCtau was the AUC from time 0 to the end of the dosing interval, where the dosing interval was 24 hours. AUCtau was calculated by the linear/log trapezoidal method using a non-compartmental PK analysis. | Cycle 2 Day 1: pre-dose and at 2, 4, 6, and 24 hours post-dose | 
| Mean Cmax for Dacomitinib and Its Metabolite PF-05199265 on Cycle 2 Day 1 for Cohort I | Cmax was obtained from direct inspection of the data. | Cycle 2 Day 1: pre-dose and at 2, 4, 6, and 24 hours post-dose | 
| Median Tmax for Dacomitinib and Its Metabolite PF-05199265 on Cycle 2 Day 1 for Cohort I | Tmax was obtained from direct inspection of the data as the time of first occurence of Cmax. | Cycle 2 Day 1: pre-dose and at 2, 4, 6, and 24 hours post-dose | 
| Mean Apparent Clearance (CL/F) for Dacomitinib on Cycle 2 Day 1 for Cohort I | CL/F was calculated as dose/AUCtau. | Cycle 2 Day 1: pre-dose and at 2, 4, 6, and 24 hours post-dose | 
| Mean Plasma Trough Concentrations (Ctrough) for Dacomitinib by Visit for Cohorts I, II and III | Ctrough was the pre-dose plasma concentration of dacomitinib at steady state obtained from direct inspection of the data. Number of participants analyzed is the total number of participants in the treatment group in the indicated population, n is the number of participants contributing to the summary statistics. | Cohorts I to III: Pre-dose on Day 1 of Cycle 3 to 10. | 
| Mean Plasma Ctrough for PF-05199265 by Visit for Cohorts I, II and III | Ctrough was the pre-dose plasma concentration of the dacomitinib metabolite PF-05199265 at steady state obtained from direct inspection of the data. Number of participants analyzed is the total number of participants in the treatment group in the indicated population, n is the number of participants contributing to the summary statistics. | Cohorts I to III: Pre-dose on Day 1 of Cycle 3 to 10. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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non-small cell lung cancer, advanced, previously treated