ARCHER 1042: 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

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01465802
• Collaborator: (none)
• Enrollment: 236
• Locations: 81
• Arms: 3
• Actual Duration (Months): 40.7
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Non Small Cell Lung Cancer (NSCLC)	Drug: Dacomitinib; Drug: Dacomitinib; Drug: Doxycycline; Drug: Probiotic; Drug: Alclometasone cream	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 236 participants
• Allocation: Non-Randomized
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Dec 26, 2011
• Actual Primary Completion Date: May 18, 2015
• Actual Study Completion Date: May 18, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort I 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; Dacomitinib 45 mg orally daily on a continuous schedule until disease progression, toxicity, death or withdrawal of consent; Drug: Doxycycline; Doxycycline or Doxycycline placebo BID for 4 weeks
Experimental: Cohort II 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; Dacomitinib 45 mg orally daily on a continuous schedule until disease progression, toxicity, death or withdrawal of consent; Drug: Probiotic; 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: Alclometasone cream; Topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks
Experimental: Cohort III Cohort III is an interrupted dosing schedule of dacomitinib in the first cycle only	Drug: Dacomitinib; 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

Outcome Measures

Primary Outcome Measures

1. 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 [First 8 Weeks of Treatment]

   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.

2. 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 [First 8 Weeks of Treatment]

   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.

3. 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 [First 8 Weeks of Treatment]

   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.

4. Percentage of Participants With Diarrhea AEs (All Causality, All Grade and Grade ≥2) in the First 8 Weeks of Treatment for Cohort II [First 8 Weeks of Treatment]

   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.

5. 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 [Cycles 1, 2, 3, 4, 5, and 6, EoT and Follow-up]

   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.

6. Percentage of Participants With SDAEI (All Causality, All Grade) in the First 8 Weeks of Treatment for Cohort II [First 8 Weeks of Treatment]

   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.

7. Percentage of Participants With SDAEI (All Causality, Grade ≥2) in the First 8 Weeks of Treatment for Cohort II [First 8 Weeks of Treatment]

   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.

8. Mean Change From Baseline (Cycle 1 Day 1) Skindex-16 Scale Scores (Total Score, Symptoms Score, Emotion Score, and Functioning Score) for Cohort II [Cycles 1, 2, 3, 4, 5, and 6, EoT and Follow-up]

   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.

9. 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 [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).]

   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

10. Mean Maximum Observed Plasma Concentrations (Cmax) for Dacomitinib and Its Metabolite PF-05199265 on Cycle 1 Days 10 to 15 for Cohort III [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).]

    Cmax was obtained from direct inspection of the data. ng/mL = nanograms per milliliter

11. Median Time of Occurrence of Cmax (Tmax) for Dacomitinib and Its Metabolite PF-05199265 on Cycle 1 Days 10 to 15 for Cohort III [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).]

    Tmax was obtained from direct inspection of the data as the time of first occurence of Cmax.

Secondary Outcome Measures

1. 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 [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)]

   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).

2. 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 [Cycle 2 Day 1: pre-dose and at 2, 4, 6, and 24 hours post-dose]

   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.

3. Mean Cmax for Dacomitinib and Its Metabolite PF-05199265 on Cycle 2 Day 1 for Cohort I [Cycle 2 Day 1: pre-dose and at 2, 4, 6, and 24 hours post-dose]

   Cmax was obtained from direct inspection of the data.

4. Median Tmax for Dacomitinib and Its Metabolite PF-05199265 on Cycle 2 Day 1 for Cohort I [Cycle 2 Day 1: pre-dose and at 2, 4, 6, and 24 hours post-dose]

   Tmax was obtained from direct inspection of the data as the time of first occurence of Cmax.

5. Mean Apparent Clearance (CL/F) for Dacomitinib on Cycle 2 Day 1 for Cohort I [Cycle 2 Day 1: pre-dose and at 2, 4, 6, and 24 hours post-dose]

   CL/F was calculated as dose/AUCtau.

6. Mean Plasma Trough Concentrations (Ctrough) for Dacomitinib by Visit for Cohorts I, II and III [Cohorts I to III: Pre-dose on Day 1 of Cycle 3 to 10.]

   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.

7. Mean Plasma Ctrough for PF-05199265 by Visit for Cohorts I, II and III [Cohorts I to III: Pre-dose on Day 1 of Cycle 3 to 10.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	St. Jude Heritage Healthcare	Fullerton	California	United States	92835
3	UCLA Hematology Oncology	Irvine	California	United States	92604
4	UC San Diego Medical Center - La Jolla	La Jolla	California	United States	92037
5	UC San Diego Moores Cancer Center - Investigational Drug Services	La Jolla	California	United States	92037
6	UC San Diego Moores Cancer Center	La Jolla	California	United States	92093
7	Drug Management Only: UCLA West Medical Pharmacy	Los Angeles	California	United States	90095-7349
8	Drug Management Only: UCLA West Medical Pharmacy Attn: Steven L. Wong, Pharm.D.	Los Angeles	California	United States	90095
9	Drug Management Only: UCLA West Medical Pharmacy	Los Angeles	California	United States	90095
10	Drug Managment Only: UCLA West Medical Pharmacy	Los Angeles	California	United States	90095
11	Regulatory Management Only TRIO-US Central Administration	Los Angeles	California	United States	90095
12	Regulatory Management Only: TRIO-US Central Administration	Los Angeles	California	United States	90095
13	Ronald Reagan UCLA Medical Center	Los Angeles	California	United States	90095
14	UCLA Hematology Oncology	Los Angeles	California	United States	90095
15	Westwood Bowyer Clinic	Los Angeles	California	United States	90095
16	UCLA/Pasadena HealthCare	Pasadena	California	United States	91105
17	UC San Diego Medical Center - Hillcrest	San Diego	California	United States	92103
18	Coastal Integrative Cancer Care	San Luis Obispo	California	United States	93401
19	SANSUM Clinic	Santa Barbara	California	United States	93105
20	Cancer Center of Santa Barbara with SANSUM Clinic	Santa Barbara	California	United States	93150
21	Central Coast Medical Oncology Corporation	Santa Maria	California	United States	93454
22	UCLA Hematology Oncology	Santa Monica	California	United States	90404
23	UCLA Santa Monica Medical Center & Orthopaedic Hospital	Santa Monica	California	United States	90404
24	Cancer Center of Santa Barbara with SANSUM Clinic	Solvang	California	United States	93463
25	City of Hope South Pasadena Cancer Center	South Pasadena	California	United States	91030
26	UCLA/Santa Clarita Valley Cancer Center	Valencia	California	United States	91355
27	UCLA Cancer Center	Westlake Village	California	United States	91361
28	Kaiser Permanente Colorado - Franklin	Denver	Colorado	United States	80205
29	St. Mary's Hospital Regional Cancer Center	Grand Junction	Colorado	United States	81501
30	Kaiser Permanente Colorado - Rock Creek	Lafayette	Colorado	United States	80026
31	Kaiser Permanente Colorado - Lonetree	Lonetree	Colorado	United States	80124
32	Michael and Dianne Bienes Comprehensive Cancer Center, Holy Cross Hospital	Fort Lauderdale	Florida	United States	33308
33	Memorial Cancer Institute	Hollywood	Florida	United States	33021
34	Cancer Care of North Florida, PA	Lake City	Florida	United States	32024
35	Memorial West Cancer Institute	Pembroke Pines	Florida	United States	33028
36	University Cancer & Blood Center, LLC	Athens	Georgia	United States	30607
37	Summit Cancer Care,PC	Savannah	Georgia	United States	31404
38	Summit Cancer Care, PC	Savannah	Georgia	United States	31405
39	Rush University Medical Center, Division of Hematology & Oncology	Chicago	Illinois	United States	60612
40	Ships Drugs to: Emmanuel Semmes, RPh (or Ami Patel, Pharm D) University of Chicago	Chicago	Illinois	United States	60637
41	University of Chicago Medical Center	Chicago	Illinois	United States	60637
42	Illinois CancerCare, P.C.	Peoria	Illinois	United States	61615
43	Cancer Center of Kansas	Wichita	Kansas	United States	67208
44	Cancer Center of Kansas	Wichita	Kansas	United States	67214
45	Josephine Ford Cancer Center-Downriver	Brownstown	Michigan	United States	48183
46	Henry Ford Medical Center - Fairlane	Dearborn	Michigan	United States	48126
47	Henry Ford Hospital	Detroit	Michigan	United States	48202
48	Henry Ford Medical Center - Columbus	Novi	Michigan	United States	48377
49	Henry Ford Hospital and Medical Center - West Bloomfield	West Bloomfield	Michigan	United States	48322
50	The West Clinic, PC	Corinth	Mississippi	United States	38834
51	The West Clinic, PC	Southaven	Mississippi	United States	38671
52	Mercy Clinic Cancer & Hematology-Branson	Branson	Missouri	United States	65616
53	Mercy Hospital Springfield	Springfield	Missouri	United States	65804
54	Mercy Clinic Cancer and Hematology - Chub O-Reilly Cancer Center	Springfield	Missouri	United States	65807
55	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89128
56	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89169
57	Saint Barnabas Medical Center	Livingston	New Jersey	United States	07039
58	Montefiore-Einstein Center for Cancer Care	Bronx	New York	United States	10461
59	Montefiore Medical Center	Bronx	New York	United States	10467
60	Beth Israel Medical Center	New York	New York	United States	10003
61	Beth Israel Comprehensive Cancer Center	New York	New York	United States	10011
62	Columbia University Medical Center - The New York Presbyterian Hospital	New York	New York	United States	10032
63	Stony Brook University Medical Center-Cancer Center	Stony Brook	New York	United States	11794-9447
64	Carolina Oncology Specialists, PA	Hickory	North Carolina	United States	28602
65	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
66	Legacy Pharma Research	Bismarck	North Dakota	United States	58501
67	Mid Dakota Clinic, PC	Bismarck	North Dakota	United States	58501
68	St Alexius Medical Center	Bismarck	North Dakota	United States	58501
69	Charleston Hematology Oncology Associates, PA	Charleston	South Carolina	United States	29414
70	The West Clinic, PC	Memphis	Tennessee	United States	38104
71	The West Clinic, PC	Memphis	Tennessee	United States	38120
72	Investigational Product Center (IPC)	Fort Worth	Texas	United States	76177
73	Investigational Products Center (IPC)	Fort Worth	Texas	United States	76177
74	'Fletcher Allen Health Care, Inc	Burlington	Vermont	United States	05401
75	Office of Clinical Trials Research, Fletcher Allen Health Care, Inc.	Burlington	Vermont	United States	05405
76	Virginia Cancer Specialists, PC	Fairfax	Virginia	United States	22031
77	Swedish Cancer Institute - Issaquah	Issaquah	Washington	United States	98029
78	Swedish Cancer Institute	Seattle	Washington	United States	98104
79	Swedish Medical Center	Seattle	Washington	United States	98122
80	Seoul National University Hospital	Seoul		Korea, Republic of	110-744
81	Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of	120-752

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01465802
• Other Study ID Numbers: A7471042
• First Posted: Nov 6, 2011
• Last Update Posted: Jan 9, 2019
• Last Verified: Dec 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Pfizer: non-small cell lung cancer; advanced; previously treated
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Doxycycline; Alclometasone dipropionate

Study Results

Participant Flow

Arm/Group Title	Cohort I: Arm A (Dacomitinib 45 mg + Doxycycline Placebo)	Cohort I: Arm B (Dacomitinib 45 mg + Doxycycline 100 mg)	Cohort I: Arm C (Dacomitinib 45mg+Alclometasone Diproprionate)	Cohort II (Dacomitinib 45mg + VSL#3 Probiotic + Alclometasone)	Cohort III (Dacomitinib 45 mg)
Arm/Group Description	Open-label dacomitinib 45 milligram (mg) tablets orally (PO) taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline placebo capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline 100 mg capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label topical alclometasone diproprionate cream 0.05 percent (%) applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label VSL#3 probiotic 4 capsules PO taken once daily or 1 sachet PO taken once daily starting on either Days -7, -6, -5 or -4 per site/participant preference, and continuing through Cycle 1 Day 28 (for a total of up to 5 weeks [range of 32 to 35 days]) PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO, taken once daily Cycle 1 Day 1 through and including Cycle 1 Day 10; no dacomitinib was taken on Cycle 1 Days 11, 12, 13 and 14; resumption of dacomitinib 45 mg PO once daily taken continuously from Cycle 1 Day 15 onwards until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal.
Period Title: Overall Study
STARTED	66	66	7	67	25
COMPLETED	33	42	7	38	13
NOT COMPLETED	33	24	0	29	12

Baseline Characteristics

Arm/Group Title	Cohort I: Arm A (Dacomitinib 45 mg + Doxycycline Placebo)	Cohort I: Arm B (Dacomitinib 45 mg + Doxycycline 100 mg)	Cohort I: Arm C (Dacomitinib 45mg+Alclometasone Diproprionate)	Cohort II (Dacomitinib 45mg + VSL#3 Probiotic + Alclometasone)	Cohort III (Dacomitinib 45 mg)	Total
Arm/Group Description	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline placebo capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline 100 mg capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label VSL#3 probiotic 4 capsules PO taken once daily or 1 sachet PO taken once daily starting on either Days -7, -6, -5 or -4 per site/participant preference, and continuing through Cycle 1 Day 28 (for a total of up to 5 weeks [range of 32 to 35 days]) PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO, taken once daily Cycle 1 Day 1 through and including Cycle 1 Day 10; no dacomitinib was taken on Cycle 1 Days 11, 12, 13 and 14; resumption of dacomitinib 45 mg PO once daily taken continuously from Cycle 1 Day 15 onwards until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal.	Total of all reporting groups
Overall Participants	66	66	7	67	25	231
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	65.0 (10.38)	64.4 (10.55)	61.3 (7.67)	66.0 (9.63)	64.2 (14.29)	64.9 (10.59)
Sex: Female, Male (Count of Participants)
Female	38 57.6%	27 40.9%	2 28.6%	24 35.8%	18 72%	109 47.2%
Male	28 42.4%	39 59.1%	5 71.4%	43 64.2%	7 28%	122 52.8%

Outcome Measures

1. Primary Outcome

Title	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
Description	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.
Time Frame	First 8 Weeks of Treatment

Outcome Measure Data

Analysis Population Description

Evaluable Population - included all participants who received the study treatment assigned at enrollment, but did not discontinue dacomitinib treatment less than 6 weeks from first dosing due to either disease progression or death.

Arm/Group Title	Cohort I: Arm A (Dacomitinib 45 mg + Doxycycline Placebo)	Cohort I: Arm B (Dacomitinib 45 mg + Doxycycline 100 mg)
Arm/Group Description	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline placebo capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline 100 mg capsules PO taken twice daily for 4 weeks (prophylactic treatment).
Measure Participants	58	56
Number (95% Confidence Interval) [Percentage of Participants]	79.3 120.2%	75.0 113.6%

2. Primary Outcome

Title	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
Description	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.
Time Frame	First 8 Weeks of Treatment

Outcome Measure Data

Analysis Population Description

Evaluable Population

Arm/Group Title	Cohort I: Arm A (Dacomitinib 45 mg + Doxycycline Placebo)	Cohort I: Arm B (Dacomitinib 45 mg + Doxycycline 100 mg)
Arm/Group Description	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline placebo capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline 100 mg capsules PO taken twice daily for 4 weeks (prophylactic treatment).
Measure Participants	58	56
Number (95% Confidence Interval) [Percentage of Participants]	46.6 70.6%	23.2 35.2%

3. Primary Outcome

Title	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
Description	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.
Time Frame	First 8 Weeks of Treatment

Outcome Measure Data

Analysis Population Description

PRO Skindex Analysis Population: participants that met primary endpoint analysis & Skindex specific criteria: a) Skindex completion criteria (as above) for initial visit & end of Cycle 2 or EoT visit; b) Skindex completion criteria for at least 5 of 6 visits between initial visit & end of Cycle 2 visit. n = number of participants completing scale.

Arm/Group Title	Cohort I: Arm A (Dacomitinib 45 mg + Doxycycline Placebo)	Cohort I: Arm B (Dacomitinib 45 mg + Doxycycline 100 mg)	Cohort I: Arm C (Dacomitinib 45mg+Alclometasone Diproprionate)
Arm/Group Description	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline placebo capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline 100 mg capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).
Measure Participants	42	42	4
Symptoms: Cycle 1 Day 8 (n=41, 42, 4)	2.3 (10.12)	-1.1 (10.91)	9.4 (14.18)
Symptoms: Cycle 1 Day 15 (n=41, 42, 3)	21.4 (30.98)	5.0 (19.82)	30.6 (42.56)
Symptoms: Cycle 1 Day 22 (n=42, 40, 4)	18.0 (25.76)	6.8 (20.45)	32.3 (25.54)
Symptoms: Cycle 2 Day 1 (n=41, 42, 4)	14.7 (23.74)	6.3 (15.38)	14.6 (18.48)
Symptoms: Cycle 2 Day 8 (n=42, 39, 4)	17.8 (26.78)	9.8 (20.00)	13.5 (19.36)
Symptoms: Cycle 2 Day 15 (n=37, 40, 4)	16.6 (21.10)	9.2 (19.54)	19.8 (28.74)
Symptoms: Cycle 2 Day 22 (n=35, 39, 4)	15.4 (22.34)	12.9 (22.72)	14.6 (15.40)
Symptoms: EoT (n=7, 3, 0)	13.1 (32.85)	16.7 (19.09)	NA (NA)
Emotion: Cycle 1 Day 8 (n=41, 42, 4)	3.7 (21.08)	-2.5 (12.11)	7.3 (14.68)
Emotion: Cycle 1 Day 15 (n=41, 42, 3)	20.7 (28.51)	2.9 (17.14)	29.8 (45.03)
Emotion: Cycle 1 Day 22 (n=42, 40, 4)	17.7 (27.67)	3.7 (16.07)	37.7 (32.44)
Emotion: Cycle 2 Day 1 (n=41, 42, 4)	15.6 (25.15)	6.5 (15.25)	23.4 (30.15)
Emotion: Cycle 2 Day 8 (n=42, 39, 4)	15.1 (25.55)	6.3 (17.28)	21.6 (35.76)
Emotion: Cycle 2 Day 15 (n=37, 40, 4)	13.0 (22.70)	8.4 (20.20)	21.0 (40.49)
Emotion: Cycle 2 Day 22 (n=35, 39, 4)	14.8 (25.91)	12.0 (23.73)	10.9 (17.39)
Emotion: EoT (n=7, 3, 0)	9.9 (21.27)	22.2 (21.34)	NA (NA)
Functioning: Cycle 1 Day 8 (n=41, 42, 4)	3.1 (17.60)	-1.2 (5.50)	-0.8 (1.67)
Functioning: Cycle 1 Day 15 (n=41, 42, 3)	11.1 (21.41)	0.6 (7.47)	24.4 (42.34)
Functioning: Cycle 1 Day 22 (n=42, 40, 4)	11.7 (21.68)	1.9 (8.86)	33.3 (31.39)
Functioning: Cycle 2 Day 1 (n=41, 42, 4)	8.5 (21.53)	2.1 (7.72)	20.0 (21.26)
Functioning: Cycle 2 Day 8 (n=42, 39, 4)	7.0 (18.51)	2.4 (9.52)	12.5 (20.79)
Functioning: Cycle 2 Day 15 (n=37, 40, 4)	8.3 (22.20)	2.7 (10.58)	13.3 (22.44)
Functioning: Cycle 2 Day 22 (n=35, 39, 4)	7.8 (22.32)	5.4 (13.78)	14.2 (20.44)
Functioning: EoT (n=7, 3, 0)	8.6 (11.84)	14.4 (25.02)	NA (NA)
Total: Cycle 1 Day 8 (n=41, 42, 4)	3.2 (15.91)	-1.7 (8.07)	5.3 (9.36)
Total: Cycle 1 Day 15 (n=41, 42, 3)	17.9 (25.09)	2.7 (13.08)	28.4 (43.52)
Total: Cycle 1 Day 22 (n=42, 40, 4)	15.9 (23.39)	4.0 (13.33)	35.0 (29.97)
Total: Cycle 2 Day 1 (n=41, 42, 4)	13.1 (20.74)	5.1 (11.65)	20.2 (21.75)
Total: Cycle 2 Day 8 (n=42, 39, 4)	13.2 (21.17)	6.0 (13.49)	16.8 (24.54)
Total: Cycle 2 Day 15 (n=37, 40, 4)	12.4 (20.39)	6.8 (14.84)	18.4 (31.50)
Total: Cycle 2 Day 22 (n=35, 39, 4)	12.7 (21.24)	10.1 (18.36)	12.9 (17.22)
Total: EoT (n=7, 3, 0)	10.3 (18.79)	18.4 (18.64)	NA (NA)

4. Primary Outcome

Title	Percentage of Participants With Diarrhea AEs (All Causality, All Grade and Grade ≥2) in the First 8 Weeks of Treatment for Cohort II
Description	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.
Time Frame	First 8 Weeks of Treatment

Outcome Measure Data

Analysis Population Description

Evaluable Population

Arm/Group Title	Cohort II (Dacomitinib 45mg + VSL#3 Probiotic + Alclometasone)
Arm/Group Description	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label VSL#3 probiotic 4 capsules PO taken once daily or 1 sachet PO taken once daily starting on either Days -7, -6, -5 or -4 per site/participant preference, and continuing through Cycle 1 Day 28 (for a total of up to 5 weeks [range of 32 to 35 days]) PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).
Measure Participants	59
All Causality, All Grade	83.1 125.9%
All Causality, Grade ≥2	39.0 59.1%

5. Primary Outcome

Title	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
Description	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.
Time Frame	Cycles 1, 2, 3, 4, 5, and 6, EoT and Follow-up

Outcome Measure Data

Analysis Population Description

PRO Modified OMDQ Analysis Population; participants meeting primary endpoint analysis & modified OMDQ specific criteria: a) Modified OMDQ completion criteria for initial visit & end of Cycle 2 or EoT visit; b) Completion criteria for at least 5 of 6 visits between initial & end of Cycle 2 visit. n = number of participants completing scale.

Arm/Group Title	Cohort II (Dacomitinib 45mg + VSL#3 Probiotic + Alclometasone)
Arm/Group Description	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label VSL#3 probiotic 4 capsules PO taken once daily or 1 sachet PO taken once daily starting on either Days -7, -6, -5 or -4 per site/participant preference, and continuing through Cycle 1 Day 28 (for a total of up to 5 weeks [range of 32 to 35 days]) PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).
Measure Participants	37
M/T Soreness Categories: Cycle 1 Day 8 (n=37)	0.8 (2.05)
M/T Soreness Categories: Cycle 1 Day 15 (n=37)	2.5 (3.12)
M/T Soreness Categories: Cycle 1 Day 22 (n=37)	2.6 (2.97)
M/T Soreness Categories: Cycle 2 Day 1 (n=37)	2.5 (2.43)
M/T Soreness Categories: Cycle 2 Day 8 (n=35)	1.9 (2.30)
M/T Soreness Categories: Cycle 2 Day 15 (n=36)	1.7 (1.97)
M/T Soreness Categories: Cycle 2 Day 22 (n=27)	1.6 (1.85)
M/T Soreness Categories: Cycle 3 Day 1 (n=19)	2.1 (2.09)
M/T Soreness Categories: Cycle 4 Day 1 (n=13)	1.7 (2.14)
M/T Soreness Categories: Cycle 5 Day 1 (n=10)	1.0 (1.29)
M/T Soreness Categories: Cycle 6 Day 1 (n=8)	0.3 (0.88)
M/T Soreness Categories: EoT (n=30)	1.4 (2.34)
M/T Soreness Categories: Follow-up (n=22)	0.3 (2.48)
M/T Soreness Scale: Cycle 1 Day 8 (n=37)	1.0 (2.00)
M/T Soreness Scale: Cycle 1 Day 15 (n=37)	2.5 (3.00)
M/T Soreness Scale: Cycle 1 Day 22 (n=37)	2.2 (2.51)
M/T Soreness Scale: Cycle 2 Day 1 (n=37)	2.2 (2.28)
M/T Soreness Scale: Cycle 2 Day 8 (n=35)	1.7 (1.97)
M/T Soreness Scale: Cycle 2 Day 15 (n=36)	1.6 (1.83)
M/T Soreness Scale: Cycle 2 Day 22 (n=27)	1.9 (2.45)
M/T Soreness Scale: Cycle 3 Day 1 (n=19)	2.2 (2.81)
M/T Soreness Scale: Cycle 4 Day 1 (n=13)	1.6 (2.81)
M/T Soreness Scale: Cycle 5 Day 1 (n=10)	1.0 (1.76)
M/T Soreness Scale: Cycle 6 Day 1 (n=8)	0.1 (0.35)
M/T Soreness Scale: EoT (n=30)	1.3 (1.78)
M/T Soreness Scale: Follow-up (n=22)	0.5 (1.68)
Diarrhea Categories: Cycle 1 Day 8 (n=37)	2.1 (2.67)
Diarrhea Categories: Cycle 1 Day 15 (n=37)	3.2 (2.94)
Diarrhea Categories: Cycle 1 Day 22 (n=36)	3.9 (3.19)
Diarrhea Categories: Cycle 2 Day 1 (n=37)	3.0 (2.83)
Diarrhea Categories: Cycle 2 Day 8 (n=34)	2.2 (3.00)
Diarrhea Categories: Cycle 2 Day 15 (n=36)	2.1 (3.13)
Diarrhea Categories: Cycle 2 Day 22 (n=27)	2.7 (3.10)
Diarrhea Categories: Cycle 3 Day 1 (n=19)	2.8 (2.75)
Diarrhea Categories: Cycle 4 Day 1 (n=13)	2.3 (3.14)
Diarrhea Categories: Cycle 5 Day 1 (n=10)	3.8 (3.39)
Diarrhea Categories: Cycle 6 Day 1 (n=8)	1.9 (2.22)
Diarrhea Categories: EoT (n=30)	1.9 (3.39)
Diarrhea Categories: Follow-up (n=22)	-0.1 (0.94)
Diarrhea Scale: Cycle 1 Day 8 (n=37)	1.2 (1.89)
Diarrhea Scale: Cycle 1 Day 15 (n=37)	2.4 (2.55)
Diarrhea Scale: Cycle 1 Day 22 (n=36)	3.0 (2.96)
Diarrhea Scale: Cycle 2 Day 1 (n=37)	2.5 (2.61)
Diarrhea Scale: Cycle 2 Day 8 (n=34)	2.0 (2.75)
Diarrhea Scale: Cycle 2 Day 15 (n=35)	1.7 (2.71)
Diarrhea Scale: Cycle 2 Day 22 (n=27)	2.0 (2.16)
Diarrhea Scale: Cycle 3 Day 1 (n=19)	2.4 (2.34)
Diarrhea Scale: Cycle 4 Day 1 (n=13)	1.8 (2.13)
Diarrhea Scale: Cycle 5 Day 1 (n=10)	2.7 (2.31)
Diarrhea Scale: Cycle 6 Day 1 (n=8)	1.5 (1.93)
Diarrhea Scale: EoT (n=30)	1.6 (2.87)
Diarrhea Scale: Follow-up (n=22)	-0.1 (0.71)

6. Primary Outcome

Title	Percentage of Participants With SDAEI (All Causality, All Grade) in the First 8 Weeks of Treatment for Cohort II
Description	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.
Time Frame	First 8 Weeks of Treatment

Outcome Measure Data

Analysis Population Description

Evaluable Population

Arm/Group Title	Cohort II (Dacomitinib 45mg + VSL#3 Probiotic + Alclometasone)
Arm/Group Description	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label VSL#3 probiotic 4 capsules PO taken once daily or 1 sachet PO taken once daily starting on either Days -7, -6, -5 or -4 per site/participant preference, and continuing through Cycle 1 Day 28 (for a total of up to 5 weeks [range of 32 to 35 days]) PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).
Measure Participants	59
Number (95% Confidence Interval) [Percentage of Participants]	79.7 120.8%

7. Primary Outcome

Title	Percentage of Participants With SDAEI (All Causality, Grade ≥2) in the First 8 Weeks of Treatment for Cohort II
Description	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.
Time Frame	First 8 Weeks of Treatment

Outcome Measure Data

Analysis Population Description

Evaluable Population

Arm/Group Title	Cohort II (Dacomitinib 45mg + VSL#3 Probiotic + Alclometasone)
Arm/Group Description	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label VSL#3 probiotic 4 capsules PO taken once daily or 1 sachet PO taken once daily starting on either Days -7, -6, -5 or -4 per site/participant preference, and continuing through Cycle 1 Day 28 (for a total of up to 5 weeks [range of 32 to 35 days]) PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).
Measure Participants	59
Number (95% Confidence Interval) [Percentage of Participants]	35.6 53.9%

8. Primary Outcome

Title	Mean Change From Baseline (Cycle 1 Day 1) Skindex-16 Scale Scores (Total Score, Symptoms Score, Emotion Score, and Functioning Score) for Cohort II
Description	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.
Time Frame	Cycles 1, 2, 3, 4, 5, and 6, EoT and Follow-up

Outcome Measure Data

Analysis Population Description

PRO Skindex Analysis Population

Arm/Group Title	Cohort II (Dacomitinib 45mg + VSL#3 Probiotic + Alclometasone)
Arm/Group Description	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label VSL#3 probiotic 4 capsules PO taken once daily or 1 sachet PO taken once daily starting on either Days -7, -6, -5 or -4 per site/participant preference, and continuing through Cycle 1 Day 28 (for a total of up to 5 weeks [range of 32 to 35 days]) PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).
Measure Participants	40
Symptoms: Cycle 1 Day 8 (n=40)	0.1 (8.31)
Symptoms: Cycle 1 Day 15 (n=40)	11.4 (21.25)
Symptoms: Cycle 1 Day 22 (n=40)	11.4 (18.17)
Symptoms: Cycle 2 Day 1 (n=40)	11.4 (19.84)
Symptoms: Cycle 2 Day 8 (n=38)	13.5 (20.88)
Symptoms: Cycle 2 Day 15 (n=38)	14.7 (17.83)
Symptoms: Cycle 2 Day 22 (n=30)	13.6 (16.30)
Symptoms: Cycle 3 Day 1 (n=21)	12.7 (19.56)
Symptoms: Cycle 4 Day 1 (n=15)	11.9 (18.69)
Symptoms: Cycle 5 Day 1 (n=11)	8.0 (22.24)
Symptoms: Cycle 6 Day 1 (n=8)	12.0 (32.15)
Symptoms: EoT (n=33)	10.4 (21.33)
Symptoms: Follow-up (n=23)	7.1 (23.15)
Emotion: Cycle 1 Day 8 (n=40)	1.0 (11.79)
Emotion: Cycle 1 Day 15 (n=40)	8.7 (23.57)
Emotion: Cycle 1 Day 22 (n=40)	12.3 (24.63)
Emotion: Cycle 2 Day 1 (n=40)	10.2 (21.36)
Emotion: Cycle 2 Day 8 (n=38)	10.3 (21.77)
Emotion: Cycle 2 Day 15 (n=37)	13.5 (17.10)
Emotion: Cycle 2 Day 22 (n= 30)	12.6 (19.86)
Emotion: Cycle 3 Day 1 (n=21)	11.0 (17.97)
Emotion: Cycle 4 Day 1 (n=14)	11.5 (14.65)
Emotion: Cycle 5 Day 1 (n=11)	7.8 (21.43)
Emotion: Cycle 6 Day 1 (n=8)	6.8 (22.67)
Emotion: EoT (n=33)	8.5 (23.38)
Emotion: Follow-up (n=23)	7.1 (22.74)
Functioning: Cycle 1 Day 8 (n=40)	0.5 (3.58)
Functioning: Cycle 1 Day 15 (n=40)	4.3 (13.34)
Functioning: Cycle 1 Day 22 (n=40)	8.8 (17.55)
Functioning: Cycle 2 Day 1 (n=40)	7.3 (15.25)
Functioning: Cycle 2 Day 8 (n=38)	6.2 (15.33)
Functioning: Cycle 2 Day 15 (n=38)	7.0 (11.75)
Functioning: Cycle 2 Day 22 (n=30)	7.2 (10.06)
Functioning: Cycle 3 Day 1 (n=21)	5.9 (8.09)
Functioning: Cycle 4 Day 1 (n=15)	6.9 (10.12)
Functioning: Cycle 5 Day 1 (n=11)	5.5 (12.93)
Functioning: Cycle 6 Day 1 (n=8)	7.1 (15.58)
Functioning: EoT (n=33)	7.7 (17.35)
Functioning: Follow-up (n=23)	5.4 (18.55)
Total: Cycle 1 Day 8 (n=40)	0.6 (6.83)
Total: Cycle 1 Day 15 (n=40)	8.0 (18.73)
Total: Cycle 1 Day 22 (n=40)	11.0 (19.59)
Total: Cycle 2 Day 1 (n=40)	9.6 (17.38)
Total: Cycle 2 Day 8 (n=38)	9.9 (17.79)
Total: Cycle 2 Day 15 (n=38)	11.8 (14.13)
Total: Cycle 2 Day 22 (n=30)	11.2 (14.14)
Total: Cycle 3 Day 1 (n=21)	9.8 (14.11)
Total: Cycle 4 Day 1 (n=15)	10.2 (12.49)
Total: Cycle 5 Day 1 (n=11)	7.1 (18.60)
Total: Cycle 6 Day 1 (n=8)	8.2 (22.43)
Total: EoT (n=33)	8.7 (19.74)
Total: Follow-up (n=23)	6.6 (20.52)

9. Secondary Outcome

Title	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
Description	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).
Time Frame	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)

Outcome Measure Data

Analysis Population Description

As Treated Population

Arm/Group Title	Cohort I: Arm A (Dacomitinib 45 mg + Doxycycline Placebo)	Cohort I: Arm B (Dacomitinib 45 mg + Doxycycline 100 mg)	Cohort I: Arm C (Dacomitinib 45mg+Alclometasone Diproprionate)	Cohort II (Dacomitinib 45mg + VSL#3 Probiotic + Alclometasone)	Cohort III (Dacomitinib 45 mg)
Arm/Group Description	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline placebo capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline 100 mg capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label VSL#3 probiotic 4 capsules PO taken once daily or 1 sachet PO taken once daily starting on either Days -7, -6, -5 or -4 per site/participant preference, and continuing through Cycle 1 Day 28 (for a total of up to 5 weeks [range of 32 to 35 days]) PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO, taken once daily Cycle 1 Day 1 through and including Cycle 1 Day 10; no dacomitinib was taken on Cycle 1 Days 11, 12, 13 and 14; resumption of dacomitinib 45 mg PO once daily taken continuously from Cycle 1 Day 15 onwards until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal.
Measure Participants	66	66	7	67	25
Any Concomitant Drug	69.7 105.6%	60.6 91.8%	85.7 1224.3%	82.1 122.5%	88.0 352%
Any Non-Drug Treatment	16.7 25.3%	16.7 25.3%	42.9 612.9%	20.9 31.2%	44.0 176%

10. Primary Outcome

Title	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
Description	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
Time Frame	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).

Outcome Measure Data

Analysis Population Description

Dose-Compliant participants only. Participants were considered dose-compliant when they received all planned doses at the same dose level right before sample collection.

Arm/Group Title	Cohort III (Dacomitinib 45 mg)
Arm/Group Description	Open-label dacomitinib 45 mg tablets PO, taken once daily Cycle 1 Day 1 through and including Cycle 1 Day 10; no dacomitinib was taken on Cycle 1 Days 11, 12, 13 and 14; resumption of dacomitinib 45 mg PO once daily taken continuously from Cycle 1 Day 15 onwards until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal.
Measure Participants	23
Dacomitinib AUC0-24	1712.88 (35)
Dacomitinib AUC0-120	5743.60 (32)
PF-05199265 AUC0-24	184.62 (139)
PF-05199265 AUC0-120	742.32 (129)

11. Primary Outcome

Title	Mean Maximum Observed Plasma Concentrations (Cmax) for Dacomitinib and Its Metabolite PF-05199265 on Cycle 1 Days 10 to 15 for Cohort III
Description	Cmax was obtained from direct inspection of the data. ng/mL = nanograms per milliliter
Time Frame	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).

Outcome Measure Data

Analysis Population Description

Dose-Compliant participants only. Participants were considered dose-compliant when they received all planned doses at the same dose level right before sample collection.

Arm/Group Title	Cohort III (Dacomitinib 45 mg)
Arm/Group Description	Open-label dacomitinib 45 mg tablets PO, taken once daily Cycle 1 Day 1 through and including Cycle 1 Day 10; no dacomitinib was taken on Cycle 1 Days 11, 12, 13 and 14; resumption of dacomitinib 45 mg PO once daily taken continuously from Cycle 1 Day 15 onwards until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal.
Measure Participants	23
Dacomitinib Cmax	79.68 (36)
PF-05199265 Cmax	8.5176 (137)

12. Primary Outcome

Title	Median Time of Occurrence of Cmax (Tmax) for Dacomitinib and Its Metabolite PF-05199265 on Cycle 1 Days 10 to 15 for Cohort III
Description	Tmax was obtained from direct inspection of the data as the time of first occurence of Cmax.
Time Frame	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).

Outcome Measure Data

Analysis Population Description

Dose-Compliant participants only. Participants were considered dose-compliant when they received all planned doses at the same dose level right before sample collection.

Arm/Group Title	Cohort III (Dacomitinib 45 mg)
Arm/Group Description	Open-label dacomitinib 45 mg tablets PO, taken once daily Cycle 1 Day 1 through and including Cycle 1 Day 10; no dacomitinib was taken on Cycle 1 Days 11, 12, 13 and 14; resumption of dacomitinib 45 mg PO once daily taken continuously from Cycle 1 Day 15 onwards until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal.
Measure Participants	23
Dacomitinib Tmax	5.850 (53)
PF-05199265 Tmax	5.980 (126)

13. Secondary Outcome

Title	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
Description	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.
Time Frame	Cycle 2 Day 1: pre-dose and at 2, 4, 6, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

Dose-Compliant participants only. Participants were considered dose-compliant when they received at least 14 consecutive doses at the same dose level right before sample collection. Number of participants analyzed is the number of participants contributing to the summary statistics.

Arm/Group Title	Cohort I: Arm A (Dacomitinib 45 mg + Doxycycline Placebo)	Cohort I: Arm B (Dacomitinib 45 mg + Doxycycline 100 mg)	Cohort I: Arm C (Dacomitinib 45mg+Alclometasone Diproprionate)
Arm/Group Description	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline placebo capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline 100 mg capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).
Measure Participants	27	27	2
Dacomitinib AUC0-tau	1801.96 (59)	1869.23 (37)	1412.42 (63)
PF-05199265 AUC0-tau	164.520 (89)	112.306 (139)	366.933 (107)

14. Secondary Outcome

Title	Mean Cmax for Dacomitinib and Its Metabolite PF-05199265 on Cycle 2 Day 1 for Cohort I
Description	Cmax was obtained from direct inspection of the data.
Time Frame	Cycle 2 Day 1: pre-dose and at 2, 4, 6, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

Dose-Compliant participants only. Participants were considered dose-compliant when they received at least 14 consecutive doses at the same dose level right before sample collection. Number of participants analyzed is the number of participants contributing to the summary statistics.

Arm/Group Title	Cohort I: Arm A (Dacomitinib 45 mg + Doxycycline Placebo)	Cohort I: Arm B (Dacomitinib 45 mg + Doxycycline 100 mg)	Cohort I: Arm C (Dacomitinib 45mg+Alclometasone Diproprionate)
Arm/Group Description	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline placebo capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline 100 mg capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).
Measure Participants	31	27	3
Dacomitinib Cmax	88.15 (57)	89.79 (36)	98.08 (89)
PF-05199265 Cmax	7.7426 (80)	5.2901 (141)	8.8545 (260)

15. Secondary Outcome

Title	Median Tmax for Dacomitinib and Its Metabolite PF-05199265 on Cycle 2 Day 1 for Cohort I
Description	Tmax was obtained from direct inspection of the data as the time of first occurence of Cmax.
Time Frame	Cycle 2 Day 1: pre-dose and at 2, 4, 6, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

Dose-Compliant participants only. Participants were considered dose-compliant when they received at least 14 consecutive doses at the same dose level right before sample collection. Number of participants analyzed is the number of participants contributing to the summary statistics.

Arm/Group Title	Cohort I: Arm A (Dacomitinib 45 mg + Doxycycline Placebo)	Cohort I: Arm B (Dacomitinib 45 mg + Doxycycline 100 mg)	Cohort I: Arm C (Dacomitinib 45mg+Alclometasone Diproprionate)
Arm/Group Description	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline placebo capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline 100 mg capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).
Measure Participants	31	27	3
Dacomitinib Tmax	4.000 (67)	6.000 (67)	6.580 (108)
PF-05199265 Tmax	4.050 (82)	4.020 (125)	6.580 (105)

16. Secondary Outcome

Title	Mean Apparent Clearance (CL/F) for Dacomitinib on Cycle 2 Day 1 for Cohort I
Description	CL/F was calculated as dose/AUCtau.
Time Frame	Cycle 2 Day 1: pre-dose and at 2, 4, 6, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

Dose-Compliant participants only. Participants were considered dose-compliant when they received at least 14 consecutive doses at the same dose level right before sample collection. Number of participants analyzed is the number of participants contributing to the summary statistics.

Arm/Group Title	Cohort I: Arm A (Dacomitinib 45 mg + Doxycycline Placebo)	Cohort I: Arm B (Dacomitinib 45 mg + Doxycycline 100 mg)	Cohort I: Arm C (Dacomitinib 45mg+Alclometasone Diproprionate)
Arm/Group Description	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline placebo capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline 100 mg capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).
Measure Participants	31	27	3
Geometric Mean (Geometric Coefficient of Variation) [Liters per hour]	29.94 (85)	24.07 (37)	34.24 (45)

17. Secondary Outcome

Title	Mean Plasma Trough Concentrations (Ctrough) for Dacomitinib by Visit for Cohorts I, II and III
Description	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.
Time Frame	Cohorts I to III: Pre-dose on Day 1 of Cycle 3 to 10.

Outcome Measure Data

Analysis Population Description

Dose-Compliant participants only. Participants were considered dose-compliant when they received at least 14 consecutive doses at the same dose level right before sample collection in Cohorts I, II and III.

Arm/Group Title	Cohort I: Arm A (Dacomitinib 45 mg + Doxycycline Placebo)	Cohort I: Arm B (Dacomitinib 45 mg + Doxycycline 100 mg)	Cohort I: Arm C (Dacomitinib 45mg+Alclometasone Diproprionate)	Cohort II (Dacomitinib 45mg + VSL#3 Probiotic + Alclometasone)	Cohort III (Dacomitinib 45 mg)
Arm/Group Description	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline placebo capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline 100 mg capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label VSL#3 probiotic 4 capsules PO taken once daily or 1 sachet PO taken once daily starting on either Days -7, -6, -5 or -4 per site/participant preference, and continuing through Cycle 1 Day 28 (for a total of up to 5 weeks [range of 32 to 35 days]) PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO, taken once daily Cycle 1 Day 1 through and including Cycle 1 Day 10; no dacomitinib was taken on Cycle 1 Days 11, 12, 13 and 14; resumption of dacomitinib 45 mg PO once daily taken continuously from Cycle 1 Day 15 onwards until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal.
Measure Participants	34	32	5	15	23
Cycle 3 Day 1 (n=13, 15, 3, 14, 15)	65.477 (50)	65.063 (55)	56.212 (46)	66.338 (58)	55.780 (40)
Cycle 4 Day 1 (n=8, 7, 2, 5, 13)	61.592 (36)	67.109 (29)	65.466 (49)	71.116 (49)	55.644 (42)
Cycle 5 Day 1 (n=3, 6, 2, 3, 12)	89.970 (38)	68.012 (39)	69.649 (63)	66.082 (33)	53.116 (44)
Cycle 6 Day 1 (n=2, 5, 1, 2, 10)	15.578 (1208)	72.856 (47)	46.000 (NA)	9.201 (3760)	52.603 (52)
Cycle 7 Day 1 (n=2, 1, 1, 1, 8)	59.086 (47)	40.900 (NA)	59.900 (NA)	42.600 (NA)	55.685 (21)
Cycle 8 Day 1 (n=2, 2, 1, 2, 8)	61.430 (90)	58.988 (31)	47.00 (NA)	64.296 (35)	51.559 (24)
Cycle 9 Day 1 (n=2, 2, 1, 2, 6)	64.747 (72)	58.928 (31)	46.000 (NA)	64.115 (30)	44.865 (50)
Cycle 10 Day 1 (n=1, 2, 1, 2, 4)	51.400 (NA)	54.041 (48)	58.800 (NA)	71.695 (26)	55.362 (32)

18. Secondary Outcome

Title	Mean Plasma Ctrough for PF-05199265 by Visit for Cohorts I, II and III
Description	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.
Time Frame	Cohorts I to III: Pre-dose on Day 1 of Cycle 3 to 10.

Outcome Measure Data

Analysis Population Description

Dose-Compliant participants only. Participants were considered dose-compliant when they received at least 14 consecutive doses at the same dose level right before sample collection in Cohorts I, II and III.

Arm/Group Title	Cohort I: Arm A (Dacomitinib 45 mg + Doxycycline Placebo)	Cohort I: Arm B (Dacomitinib 45 mg + Doxycycline 100 mg)	Cohort I: Arm C (Dacomitinib 45mg+Alclometasone Diproprionate)	Cohort II (Dacomitinib 45mg + VSL#3 Probiotic + Alclometasone)	Cohort III (Dacomitinib 45 mg)
Arm/Group Description	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline placebo capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline 100 mg capsules PO taken twice daily for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label VSL#3 probiotic 4 capsules PO taken once daily or 1 sachet PO taken once daily starting on either Days -7, -6, -5 or -4 per site/participant preference, and continuing through Cycle 1 Day 28 (for a total of up to 5 weeks [range of 32 to 35 days]) PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).	Open-label dacomitinib 45 mg tablets PO, taken once daily Cycle 1 Day 1 through and including Cycle 1 Day 10; no dacomitinib was taken on Cycle 1 Days 11, 12, 13 and 14; resumption of dacomitinib 45 mg PO once daily taken continuously from Cycle 1 Day 15 onwards until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal.
Measure Participants	34	32	5	15	23
Cycle 3 Day 1 (n=13, 15, 3, 14, 15)	6.988 (60)	4.653 (133)	10.220 (11)	7.814 (59)	9.967 (149)
Cycle 4 Day 1 (n=8, 7, 2, 5, 13)	5.555 (71)	5.271 (242)	8.522 (15)	6.848 (82)	11.759 (113)
Cycle 5 Day 1 (n=3, 6, 2, 3, 12)	4.356 (55)	4.989 (58)	8.522 (10)	5.850 (115)	10.510 (124)
Cycle 6 Day 1 (n=2, 5, 1, 2, 10)	5.020 (70)	6.523 (123)	8.150 (NA)	1.261 (937)	7.844 (125)
Cycle 7 Day 1 (n=2, 1, 1, 1, 8)	4.850 (49)	23.900 (NA)	8.560 (NA)	6.680 (NA)	8.203 (105)
Cycle 8 Day 1 (n=2, 2, 1, 2, 8)	5.349 (54)	6.085 (476)	10.100 (NA)	10.844 (38)	8.205 (117)
Cycle 9 Day 1 (n=2, 2, 1, 2, 6)	4.271 (34)	6.448 (612)	9.720 (NA)	9.159 (58)	6.963 (88)
Cycle 10 Day 1 (n=1, 2, 1, 2, 4)	3.460 (NA)	6.892 (305)	10.700 (NA)	9.442 (26)	6.364 (154)

Adverse Events

Time Frame	Reported AEs and serious AEs (SAEs) included events starting from the time participant had taken at least 1 dose of study drug through and including 28 calendar days after the last dose of study drug, with a median of 12 weeks.
Adverse Event Reporting Description	The same event may appear as both an AE & SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant & non-serious in another, or 1 participant may have experienced both a serious & non-serious event during the study. Summaries inclusive of events occurring after start of treatment.
Arm/Group Title	Cohort I: Arm A (Dacomitinib 45 mg + Doxycycline Placebo)		Cohort I: Arm B (Dacomitinib 45 mg + Doxycycline 100 mg)		Cohort I: Arm C (Dacomitinib 45mg+Alclometasone Diproprionate)		Cohort II (Dacomitinib 45mg + VSL#3 Probiotic + Alclometasone)		Cohort III (Dacomitinib 45 mg)
Arm/Group Description	Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline placebo capsules PO taken twice daily for 4 weeks (prophylactic treatment).		Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline 100 mg capsules PO taken twice daily for 4 weeks (prophylactic treatment).		Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).		Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label VSL#3 probiotic 4 capsules PO taken once daily or 1 sachet PO taken once daily starting on either Days -7, -6, -5 or -4 per site/participant preference, and continuing through Cycle 1 Day 28 (for a total of up to 5 weeks [range of 32 to 35 days]) PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).		Open-label dacomitinib 45 mg tablets PO, taken once daily Cycle 1 Day 1 through and including Cycle 1 Day 10; no dacomitinib was taken on Cycle 1 Days 11, 12, 13 and 14; resumption of dacomitinib 45 mg PO once daily taken continuously from Cycle 1 Day 15 onwards until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal.
All Cause Mortality
	Cohort I: Arm A (Dacomitinib 45 mg + Doxycycline Placebo)		Cohort I: Arm B (Dacomitinib 45 mg + Doxycycline 100 mg)		Cohort I: Arm C (Dacomitinib 45mg+Alclometasone Diproprionate)		Cohort II (Dacomitinib 45mg + VSL#3 Probiotic + Alclometasone)		Cohort III (Dacomitinib 45 mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Cohort I: Arm A (Dacomitinib 45 mg + Doxycycline Placebo)		Cohort I: Arm B (Dacomitinib 45 mg + Doxycycline 100 mg)		Cohort I: Arm C (Dacomitinib 45mg+Alclometasone Diproprionate)		Cohort II (Dacomitinib 45mg + VSL#3 Probiotic + Alclometasone)		Cohort III (Dacomitinib 45 mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/66 (37.9%)		27/66 (40.9%)		3/7 (42.9%)		22/67 (32.8%)		6/25 (24%)
Blood and lymphatic system disorders
Anaemia	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		1/67 (1.5%)		1/25 (4%)
Febrile neutropenia	0/66 (0%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		1/25 (4%)
Leukocytosis	0/66 (0%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Pancytopenia	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Cardiac disorders
Cardiac arrest	0/66 (0%)		0/66 (0%)		0/7 (0%)		1/67 (1.5%)		0/25 (0%)
Cardiac tamponade	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Cardio-respiratory arrest	0/66 (0%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Cardiogenic shock	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Myocardial infarction	0/66 (0%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Pericardial effusion	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Supraventricular tachycardia	0/66 (0%)		2/66 (3%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Eye disorders
Diplopia	0/66 (0%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Gastrointestinal disorders
Abdominal pain	0/66 (0%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Constipation	1/66 (1.5%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Diarrhoea	1/66 (1.5%)		2/66 (3%)		1/7 (14.3%)		1/67 (1.5%)		1/25 (4%)
Duodenal ulcer perforation	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		1/67 (1.5%)		0/25 (0%)
Gastrointestinal haemorrhage	1/66 (1.5%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Intestinal obstruction	1/66 (1.5%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Intra-abdominal haemorrhage	0/66 (0%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Nausea	0/66 (0%)		4/66 (6.1%)		0/7 (0%)		1/67 (1.5%)		1/25 (4%)
Small intestinal obstruction	0/66 (0%)		0/66 (0%)		0/7 (0%)		1/67 (1.5%)		0/25 (0%)
Vomiting	0/66 (0%)		3/66 (4.5%)		0/7 (0%)		2/67 (3%)		1/25 (4%)
General disorders
Asthenia	2/66 (3%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Chest pain	0/66 (0%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		1/25 (4%)
Disease progression	7/66 (10.6%)		7/66 (10.6%)		0/7 (0%)		8/67 (11.9%)		1/25 (4%)
Mucosal inflammation	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Non-cardiac chest pain	0/66 (0%)		0/66 (0%)		0/7 (0%)		1/67 (1.5%)		0/25 (0%)
Pain	2/66 (3%)		1/66 (1.5%)		0/7 (0%)		1/67 (1.5%)		0/25 (0%)
Pyrexia	0/66 (0%)		1/66 (1.5%)		0/7 (0%)		1/67 (1.5%)		0/25 (0%)
Infections and infestations
Acute sinusitis	0/66 (0%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		1/25 (4%)
Cholecystitis infective	0/66 (0%)		0/66 (0%)		0/7 (0%)		1/67 (1.5%)		0/25 (0%)
Clostridium difficile colitis	0/66 (0%)		0/66 (0%)		0/7 (0%)		1/67 (1.5%)		0/25 (0%)
Enterocolitis infectious	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Gastroenteritis	0/66 (0%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Osteomyelitis	0/66 (0%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Pneumonia	2/66 (3%)		0/66 (0%)		1/7 (14.3%)		5/67 (7.5%)		1/25 (4%)
Septic shock	2/66 (3%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Injury, poisoning and procedural complications
Fall	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		1/25 (4%)
Femoral neck fracture	0/66 (0%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Femur fracture	0/66 (0%)		0/66 (0%)		0/7 (0%)		1/67 (1.5%)		0/25 (0%)
Rib fracture	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Spinal fracture	0/66 (0%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		1/25 (4%)
Toxicity to various agents	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Investigations
Blood creatinine increased	0/66 (0%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Platelet count decreased	0/66 (0%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		1/25 (4%)
Weight decreased	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Metabolism and nutrition disorders
Dehydration	5/66 (7.6%)		3/66 (4.5%)		0/7 (0%)		1/67 (1.5%)		1/25 (4%)
Electrolyte imbalance	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Hypokalaemia	0/66 (0%)		0/66 (0%)		0/7 (0%)		1/67 (1.5%)		1/25 (4%)
Metabolic acidosis	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Metabolic alkalosis	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/66 (0%)		0/66 (0%)		0/7 (0%)		1/67 (1.5%)		0/25 (0%)
Back pain	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung cancer metastatic	1/66 (1.5%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Malignant pleural effusion	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Non-small cell lung cancer metastatic	0/66 (0%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Pancreatic carcinoma	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Nervous system disorders
Aphasia	0/66 (0%)		0/66 (0%)		0/7 (0%)		1/67 (1.5%)		0/25 (0%)
Cerebral haemorrhage	0/66 (0%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Cerebral infarction	0/66 (0%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Cerebrovascular accident	1/66 (1.5%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Transient ischaemic attack	0/66 (0%)		1/66 (1.5%)		0/7 (0%)		1/67 (1.5%)		0/25 (0%)
Renal and urinary disorders
Acute kidney injury	3/66 (4.5%)		0/66 (0%)		1/7 (14.3%)		1/67 (1.5%)		0/25 (0%)
Haematuria	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Hydronephrosis	0/66 (0%)		0/66 (0%)		0/7 (0%)		1/67 (1.5%)		0/25 (0%)
Renal impairment	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/66 (0%)		0/66 (0%)		0/7 (0%)		1/67 (1.5%)		0/25 (0%)
Dyspnoea	1/66 (1.5%)		2/66 (3%)		1/7 (14.3%)		1/67 (1.5%)		1/25 (4%)
Hypoxia	0/66 (0%)		0/66 (0%)		0/7 (0%)		1/67 (1.5%)		0/25 (0%)
Pleural effusion	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Pleuritic pain	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Pneumonitis	0/66 (0%)		2/66 (3%)		0/7 (0%)		1/67 (1.5%)		0/25 (0%)
Pneumothorax	2/66 (3%)		2/66 (3%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Pulmonary embolism	0/66 (0%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Respiratory distress	0/66 (0%)		0/66 (0%)		0/7 (0%)		1/67 (1.5%)		0/25 (0%)
Respiratory failure	0/66 (0%)		2/66 (3%)		0/7 (0%)		1/67 (1.5%)		0/25 (0%)
Skin and subcutaneous tissue disorders
Perivascular dermatitis	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Subcutaneous emphysema	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Vascular disorders
Deep vein thrombosis	0/66 (0%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Embolism	0/66 (0%)		1/66 (1.5%)		1/7 (14.3%)		0/67 (0%)		1/25 (4%)
Hypotension	0/66 (0%)		1/66 (1.5%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Hypovolaemic shock	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	Cohort I: Arm A (Dacomitinib 45 mg + Doxycycline Placebo)		Cohort I: Arm B (Dacomitinib 45 mg + Doxycycline 100 mg)		Cohort I: Arm C (Dacomitinib 45mg+Alclometasone Diproprionate)		Cohort II (Dacomitinib 45mg + VSL#3 Probiotic + Alclometasone)		Cohort III (Dacomitinib 45 mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	65/66 (98.5%)		66/66 (100%)		7/7 (100%)		64/67 (95.5%)		25/25 (100%)
Blood and lymphatic system disorders
Anaemia	10/66 (15.2%)		7/66 (10.6%)		3/7 (42.9%)		5/67 (7.5%)		3/25 (12%)
Cardiac disorders
Tachycardia	1/66 (1.5%)		4/66 (6.1%)		0/7 (0%)		3/67 (4.5%)		0/25 (0%)
Ear and labyrinth disorders
Deafness	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		1/67 (1.5%)		0/25 (0%)
Tinnitus	1/66 (1.5%)		0/66 (0%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Eye disorders
Dry eye	5/66 (7.6%)		4/66 (6.1%)		0/7 (0%)		2/67 (3%)		3/25 (12%)
Eye pain	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		0/67 (0%)		2/25 (8%)
Ocular hyperaemia	2/66 (3%)		0/66 (0%)		0/7 (0%)		1/67 (1.5%)		2/25 (8%)
Vision blurred	0/66 (0%)		1/66 (1.5%)		2/7 (28.6%)		0/67 (0%)		1/25 (4%)
Gastrointestinal disorders
Abdominal distension	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		2/67 (3%)		2/25 (8%)
Abdominal pain	7/66 (10.6%)		7/66 (10.6%)		0/7 (0%)		3/67 (4.5%)		3/25 (12%)
Abdominal pain upper	4/66 (6.1%)		3/66 (4.5%)		0/7 (0%)		2/67 (3%)		2/25 (8%)
Cheilitis	3/66 (4.5%)		1/66 (1.5%)		1/7 (14.3%)		3/67 (4.5%)		1/25 (4%)
Constipation	9/66 (13.6%)		14/66 (21.2%)		2/7 (28.6%)		8/67 (11.9%)		3/25 (12%)
Diarrhoea	54/66 (81.8%)		52/66 (78.8%)		7/7 (100%)		54/67 (80.6%)		23/25 (92%)
Dry mouth	4/66 (6.1%)		5/66 (7.6%)		1/7 (14.3%)		4/67 (6%)		6/25 (24%)
Dyspepsia	3/66 (4.5%)		10/66 (15.2%)		0/7 (0%)		2/67 (3%)		3/25 (12%)
Food poisoning	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Gastritis	1/66 (1.5%)		0/66 (0%)		1/7 (14.3%)		1/67 (1.5%)		0/25 (0%)
Glossodynia	0/66 (0%)		4/66 (6.1%)		0/7 (0%)		1/67 (1.5%)		0/25 (0%)
Haemorrhoids	0/66 (0%)		1/66 (1.5%)		0/7 (0%)		1/67 (1.5%)		2/25 (8%)
Lip swelling	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		1/67 (1.5%)		0/25 (0%)
Nausea	28/66 (42.4%)		31/66 (47%)		2/7 (28.6%)		20/67 (29.9%)		4/25 (16%)
Oesophagitis	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Oral mucosal erythema	2/66 (3%)		0/66 (0%)		1/7 (14.3%)		1/67 (1.5%)		0/25 (0%)
Oral pain	2/66 (3%)		4/66 (6.1%)		0/7 (0%)		7/67 (10.4%)		2/25 (8%)
Stomatitis	10/66 (15.2%)		12/66 (18.2%)		3/7 (42.9%)		14/67 (20.9%)		16/25 (64%)
Vomiting	16/66 (24.2%)		23/66 (34.8%)		3/7 (42.9%)		14/67 (20.9%)		5/25 (20%)
General disorders
Asthenia	4/66 (6.1%)		7/66 (10.6%)		2/7 (28.6%)		3/67 (4.5%)		1/25 (4%)
Chest discomfort	2/66 (3%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		2/25 (8%)
Chills	5/66 (7.6%)		0/66 (0%)		4/7 (57.1%)		1/67 (1.5%)		1/25 (4%)
Fatigue	24/66 (36.4%)		27/66 (40.9%)		3/7 (42.9%)		20/67 (29.9%)		5/25 (20%)
Influenza like illness	1/66 (1.5%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		4/25 (16%)
Malaise	0/66 (0%)		2/66 (3%)		1/7 (14.3%)		1/67 (1.5%)		0/25 (0%)
Mucosal inflammation	19/66 (28.8%)		21/66 (31.8%)		2/7 (28.6%)		12/67 (17.9%)		5/25 (20%)
Oedema peripheral	6/66 (9.1%)		4/66 (6.1%)		1/7 (14.3%)		4/67 (6%)		3/25 (12%)
Pain	5/66 (7.6%)		7/66 (10.6%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Pyrexia	3/66 (4.5%)		4/66 (6.1%)		1/7 (14.3%)		0/67 (0%)		4/25 (16%)
Hepatobiliary disorders
Cholelithiasis	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Immune system disorders
Immunosuppression	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Infections and infestations
Bronchitis	2/66 (3%)		2/66 (3%)		0/7 (0%)		1/67 (1.5%)		2/25 (8%)
Cellulitis	1/66 (1.5%)		1/66 (1.5%)		1/7 (14.3%)		0/67 (0%)		2/25 (8%)
Cystitis	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		1/67 (1.5%)		1/25 (4%)
Folliculitis	0/66 (0%)		1/66 (1.5%)		2/7 (28.6%)		0/67 (0%)		0/25 (0%)
Fungal skin infection	1/66 (1.5%)		2/66 (3%)		0/7 (0%)		4/67 (6%)		0/25 (0%)
Herpes zoster	1/66 (1.5%)		1/66 (1.5%)		1/7 (14.3%)		0/67 (0%)		2/25 (8%)
Mucosal infection	1/66 (1.5%)		0/66 (0%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Otitis externa	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Paronychia	12/66 (18.2%)		10/66 (15.2%)		3/7 (42.9%)		9/67 (13.4%)		16/25 (64%)
Pneumonia	2/66 (3%)		2/66 (3%)		1/7 (14.3%)		2/67 (3%)		2/25 (8%)
Rash pustular	4/66 (6.1%)		2/66 (3%)		0/7 (0%)		7/67 (10.4%)		2/25 (8%)
Upper respiratory tract infection	2/66 (3%)		1/66 (1.5%)		0/7 (0%)		3/67 (4.5%)		7/25 (28%)
Urinary tract infection	8/66 (12.1%)		7/66 (10.6%)		1/7 (14.3%)		2/67 (3%)		3/25 (12%)
Vulvovaginal mycotic infection	1/66 (1.5%)		2/66 (3%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Injury, poisoning and procedural complications
Contusion	3/66 (4.5%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		2/25 (8%)
Fall	5/66 (7.6%)		0/66 (0%)		0/7 (0%)		1/67 (1.5%)		1/25 (4%)
Limb injury	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Rib fracture	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Investigations
Alanine aminotransferase increased	2/66 (3%)		0/66 (0%)		2/7 (28.6%)		2/67 (3%)		3/25 (12%)
Aspartate aminotransferase increased	6/66 (9.1%)		1/66 (1.5%)		1/7 (14.3%)		3/67 (4.5%)		3/25 (12%)
Blood alkaline phosphatase increased	3/66 (4.5%)		1/66 (1.5%)		0/7 (0%)		4/67 (6%)		1/25 (4%)
Blood creatinine increased	8/66 (12.1%)		5/66 (7.6%)		1/7 (14.3%)		3/67 (4.5%)		1/25 (4%)
Transaminases increased	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Weight decreased	15/66 (22.7%)		15/66 (22.7%)		2/7 (28.6%)		8/67 (11.9%)		7/25 (28%)
Metabolism and nutrition disorders
Decreased appetite	24/66 (36.4%)		22/66 (33.3%)		3/7 (42.9%)		25/67 (37.3%)		14/25 (56%)
Dehydration	15/66 (22.7%)		15/66 (22.7%)		1/7 (14.3%)		9/67 (13.4%)		1/25 (4%)
Hyperkalaemia	0/66 (0%)		1/66 (1.5%)		1/7 (14.3%)		2/67 (3%)		0/25 (0%)
Hypermagnesaemia	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		1/67 (1.5%)		0/25 (0%)
Hypoalbuminaemia	8/66 (12.1%)		1/66 (1.5%)		1/7 (14.3%)		2/67 (3%)		2/25 (8%)
Hypokalaemia	9/66 (13.6%)		10/66 (15.2%)		0/7 (0%)		10/67 (14.9%)		2/25 (8%)
Hypomagnesaemia	7/66 (10.6%)		14/66 (21.2%)		1/7 (14.3%)		8/67 (11.9%)		1/25 (4%)
Hyponatraemia	4/66 (6.1%)		7/66 (10.6%)		2/7 (28.6%)		2/67 (3%)		2/25 (8%)
Hypophosphataemia	2/66 (3%)		1/66 (1.5%)		1/7 (14.3%)		0/67 (0%)		1/25 (4%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/66 (3%)		7/66 (10.6%)		0/7 (0%)		4/67 (6%)		0/25 (0%)
Back pain	3/66 (4.5%)		5/66 (7.6%)		1/7 (14.3%)		6/67 (9%)		3/25 (12%)
Flank pain	2/66 (3%)		1/66 (1.5%)		0/7 (0%)		0/67 (0%)		2/25 (8%)
Muscle spasms	4/66 (6.1%)		6/66 (9.1%)		1/7 (14.3%)		1/67 (1.5%)		2/25 (8%)
Musculoskeletal chest pain	3/66 (4.5%)		4/66 (6.1%)		0/7 (0%)		5/67 (7.5%)		1/25 (4%)
Musculoskeletal pain	2/66 (3%)		1/66 (1.5%)		1/7 (14.3%)		6/67 (9%)		6/25 (24%)
Myalgia	1/66 (1.5%)		2/66 (3%)		0/7 (0%)		0/67 (0%)		5/25 (20%)
Pain in extremity	3/66 (4.5%)		4/66 (6.1%)		0/7 (0%)		1/67 (1.5%)		2/25 (8%)
Nervous system disorders
Dizziness	6/66 (9.1%)		2/66 (3%)		1/7 (14.3%)		2/67 (3%)		4/25 (16%)
Dysgeusia	5/66 (7.6%)		7/66 (10.6%)		0/7 (0%)		7/67 (10.4%)		2/25 (8%)
Headache	5/66 (7.6%)		5/66 (7.6%)		1/7 (14.3%)		1/67 (1.5%)		5/25 (20%)
Hypoaesthesia	1/66 (1.5%)		2/66 (3%)		0/7 (0%)		0/67 (0%)		4/25 (16%)
Psychiatric disorders
Anxiety	4/66 (6.1%)		3/66 (4.5%)		1/7 (14.3%)		3/67 (4.5%)		1/25 (4%)
Confusional state	2/66 (3%)		1/66 (1.5%)		0/7 (0%)		2/67 (3%)		2/25 (8%)
Insomnia	4/66 (6.1%)		9/66 (13.6%)		1/7 (14.3%)		3/67 (4.5%)		4/25 (16%)
Renal and urinary disorders
Dysuria	1/66 (1.5%)		0/66 (0%)		1/7 (14.3%)		1/67 (1.5%)		0/25 (0%)
Haematuria	3/66 (4.5%)		1/66 (1.5%)		0/7 (0%)		5/67 (7.5%)		3/25 (12%)
Pollakiuria	1/66 (1.5%)		1/66 (1.5%)		1/7 (14.3%)		3/67 (4.5%)		1/25 (4%)
Proteinuria	1/66 (1.5%)		0/66 (0%)		1/7 (14.3%)		0/67 (0%)		1/25 (4%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/66 (0%)		0/66 (0%)		0/7 (0%)		1/67 (1.5%)		3/25 (12%)
Genital rash	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		1/67 (1.5%)		0/25 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	8/66 (12.1%)		6/66 (9.1%)		3/7 (42.9%)		7/67 (10.4%)		8/25 (32%)
Dysphonia	2/66 (3%)		0/66 (0%)		0/7 (0%)		3/67 (4.5%)		2/25 (8%)
Dyspnoea	8/66 (12.1%)		9/66 (13.6%)		2/7 (28.6%)		8/67 (11.9%)		4/25 (16%)
Epistaxis	10/66 (15.2%)		4/66 (6.1%)		1/7 (14.3%)		6/67 (9%)		7/25 (28%)
Haemoptysis	4/66 (6.1%)		6/66 (9.1%)		0/7 (0%)		3/67 (4.5%)		2/25 (8%)
Hiccups	0/66 (0%)		1/66 (1.5%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Nasal congestion	1/66 (1.5%)		1/66 (1.5%)		0/7 (0%)		1/67 (1.5%)		5/25 (20%)
Oropharyngeal pain	5/66 (7.6%)		2/66 (3%)		1/7 (14.3%)		2/67 (3%)		2/25 (8%)
Pleural effusion	4/66 (6.1%)		2/66 (3%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Productive cough	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		2/67 (3%)		7/25 (28%)
Rhinitis allergic	1/66 (1.5%)		3/66 (4.5%)		0/7 (0%)		2/67 (3%)		7/25 (28%)
Rhinorrhoea	7/66 (10.6%)		2/66 (3%)		2/7 (28.6%)		3/67 (4.5%)		4/25 (16%)
Sputum increased	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Skin and subcutaneous tissue disorders
Alopecia	2/66 (3%)		4/66 (6.1%)		0/7 (0%)		3/67 (4.5%)		4/25 (16%)
Dermatitis acneiform	16/66 (24.2%)		12/66 (18.2%)		2/7 (28.6%)		20/67 (29.9%)		18/25 (72%)
Dry skin	27/66 (40.9%)		19/66 (28.8%)		2/7 (28.6%)		15/67 (22.4%)		14/25 (56%)
Erythema	12/66 (18.2%)		10/66 (15.2%)		1/7 (14.3%)		7/67 (10.4%)		3/25 (12%)
Hypertrichosis	0/66 (0%)		0/66 (0%)		2/7 (28.6%)		1/67 (1.5%)		0/25 (0%)
Ingrowing nail	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		1/67 (1.5%)		0/25 (0%)
Palmar-plantar erythrodysaesthesia syndrome	7/66 (10.6%)		5/66 (7.6%)		0/7 (0%)		4/67 (6%)		6/25 (24%)
Papule	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		2/67 (3%)		1/25 (4%)
Pruritus	7/66 (10.6%)		13/66 (19.7%)		3/7 (42.9%)		13/67 (19.4%)		17/25 (68%)
Pruritus generalised	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		2/67 (3%)		0/25 (0%)
Rash	28/66 (42.4%)		29/66 (43.9%)		5/7 (71.4%)		25/67 (37.3%)		5/25 (20%)
Rash erythematous	1/66 (1.5%)		1/66 (1.5%)		1/7 (14.3%)		1/67 (1.5%)		1/25 (4%)
Rash maculo-papular	3/66 (4.5%)		8/66 (12.1%)		1/7 (14.3%)		8/67 (11.9%)		7/25 (28%)
Rash papular	2/66 (3%)		4/66 (6.1%)		0/7 (0%)		0/67 (0%)		2/25 (8%)
Skin exfoliation	5/66 (7.6%)		8/66 (12.1%)		0/7 (0%)		5/67 (7.5%)		0/25 (0%)
Skin fissures	2/66 (3%)		6/66 (9.1%)		1/7 (14.3%)		9/67 (13.4%)		5/25 (20%)
Skin lesion	4/66 (6.1%)		0/66 (0%)		0/7 (0%)		2/67 (3%)		0/25 (0%)
Trichorrhexis	0/66 (0%)		0/66 (0%)		2/7 (28.6%)		0/67 (0%)		0/25 (0%)
Vascular disorders
Hyperaemia	0/66 (0%)		0/66 (0%)		1/7 (14.3%)		0/67 (0%)		0/25 (0%)
Hypertension	0/66 (0%)		0/66 (0%)		0/7 (0%)		0/67 (0%)		2/25 (8%)
Hypotension	9/66 (13.6%)		3/66 (4.5%)		1/7 (14.3%)		4/67 (6%)		0/25 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.