BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01248247
• Collaborator: Merck Sharp & Dohme LLC (Industry), National Cancer Institute (NCI) (NIH), GlaxoSmithKline (Industry), Novartis (Industry)
• Enrollment: 334
• Locations: 2
• Arms: 4
• Actual Duration (Months): 114
• Patients Per Site: 167
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

Different people have different biomarkers (chemical "markers" in the blood that may be related to your reaction to study drugs). If researchers know about your biomarkers before you receive treatment, they may be able to prescribe a treatment that is better suited to your body's specific needs.

The goal of this clinical research study is to learn if drug or drug combinations based on your biomarkers can help to control NSCLC. The safety of these drug combinations will also be studied.

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer	Drug: Erlotinib; Drug: AZD6244; Drug: MK-2206; Drug: Sorafenib; Drug: Erlotinib; Drug: MK-2206	Phase 2

Detailed Description

The Study Drugs:

Erlotinib hydrochloride, MK-2206, AZD6244, and Sorafenib are targeted therapies. Targeted therapy is a type of drug that blocks the growth of cancer cells by interfering with specific targeted molecules needed for tumor growth, rather than by simply interfering with rapidly dividing cells (for example with traditional chemotherapy).

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to 1 of 4 groups:

• If you are in Group 1, you will take erlotinib alone.

• If you are in Group 2, you will take erlotinib and MK-2206.

• If you are in Group 3, you will take AZD6244 and MK-2206.

• If you are in Group 4, you will take sorafenib alone.

The group you are in will be assigned by a computer. The results of your screening tests will be used to determine (and may limit) which of the 4 groups you may be eligible to be assigned to. Your likelihood of being in any 1 group over another may also be affected by how well that treatment has done in earlier study participants. Your study doctor will tell you which group you have been assigned.

Study Drug Administration:

Each cycle is 28 days.

• If you are in Group 1, you will take erlotinib hydrochloride by mouth 1 time every day.

• If you are in Group 2, you will take MK-2206 by mouth 1 time every week. You will take erlotinib hydrochloride by mouth 1 time every day.

• If you are in Group 3, you will take MK-2206 by mouth 1 time per week. You will take AZD6244 by mouth 1 time every day.

• If you are in Group 4, you will take sorafenib by mouth 2 times every day.

If you will take erlotinib hydrochloride (Groups 1 and 2), you should take the tablets in the morning. You should take the drug 1 hour before or 2 hours after a meal, with no more than 7 ounces of water. If you forget to take a dose, the last missed dose should be taken as soon as you remember, as long as it is at least 12 hours before the next dose. The next day, you should take the scheduled dose at the usual time. You should try not to vomit for at least 30 minutes after taking the drug. If you feel nauseated before or after taking the erlotinib, you should take an anti-nausea drug. You may take an extra dose of erlotinib if you vomit within 30 minutes after taking the tablet.

If you are in Group 2, you should take MK-2206 at about the same time each week with about 1 cup (8 ounces) of water. You must take MK-2206 at least 2 hours before or at least 2 hours after any food or a meal. You should not make up any missed doses.

If you are in Group 3, you should take MK-2206 at about the same time each week with about 1 cup (8 ounces) of water. You must take MK-2206 at least 2 hours before or at least 2 hours after eating. You should not make up any missed doses.

If you will take AZD6244 (Group 3), you should take the study drug in the morning before you eat or drink anything. You can eat breakfast 1 hour after you take the dose.

If you will take sorafenib, you must take your doses 12 hours apart. You will take 2 tablets each morning, and again each evening. Sorafenib should be taken with about 1 cup of water on an empty stomach (either 1 hour before a meal or 2 hours after a meal). If you feel nauseated before or after taking the medication, anti-nausea medications should be used. If you miss a dose, you should skip it and take the next scheduled dose at the right time.

Your medication should be stored at room temperature.

Study Visits:

The study visit schedule is described below. In certain cases, with the permission of your doctor, the study visits may occur up to 7 days earlier or later than described below.

On Day 1 of each cycle:

• You will have a complete physical exam, including measurement of your weight and vital signs.

• You will be asked about any drugs you may be taking and any side effects you may be having.

• Your performance status will be recorded.

• Blood (about 3 teaspoons) will be drawn for routine tests. If your doctor thinks it is needed, you may have to have these blood tests more often.

On Day 1 of every odd-numbered cycle (Cycles 3, 5, 7, and so on):

• You will have a CT scan and/or MRI of the chest (and abdomen if the doctor thinks it is needed) to check the status of the disease.

• You will have a chest x-ray.

• MRI of the brain (if the doctor thinks it is needed)

Additional Tests for Group 2:

• During screening, on Day 1 of Cycle 2, and at the end-of study visit, you will have an eye exam.

• On Day 1 of Cycle 1 you will have an ECG before taking your study medication and then again about 4 hours after you take your study medication.

Additional Tests for Group 3:

• During screening, on Day 1 of Cycle 2, and at the end-of study visit, you will have an eye exam.

• During Cycle 2 (Week 6 of being on study drug), on Day 1 of Cycle 4, and then every 3 months, you will have a multigated acquisition (MUGA) scan and/or echocardiogram to check your heart function. You will have these tests more often if the doctor thinks it is needed.

• On Day 1 of Cycle 1 you will have an ECG before taking your study medication and then again about 4 hours after you take your study medication.

Length of Study:

You may continue to take the study drug(s) for as long as you are benefitting. You will be taken off study if the disease gets worse or if you have intolerable side effects.

End-of-Study Visit:

When you go off study for any reason, you will have an end-of-study. This visit may occur up to 7 days earlier or later. The following tests and procedures will be performed:

• Your medical history will be recorded.

• You will have a complete physical exam, including measurement of your weight and vital signs.

• You will be asked about any drugs you may be taking and any side effects you may be having.

• Your performance status will be recorded.

• Blood (about 3 teaspoons) and urine will be collected for routine tests.

• You will have a CT scan and/or MRI of the chest (and abdomen if the doctor thinks it is needed) to check the status of the disease.

• You will have a chest x-ray.

• You will have an ECG (Group 3).

Follow-Up:

You will have a follow-up evaluation performed 4 weeks ± 7 days after therapy is discontinued. This evaluation may be a visit or contact by phone by the research personnel. If you are in Group 3, you will have a MUGA scan and/or echocardiogram to check your heart function.

You will be called every 3 months for up to 3 years and asked about any cancer treatments you may be receiving. This phone call will take about 10 minutes.

This is an investigational study. Erlotinib is FDA approved and commercially available for treatment of NSCLC that has gotten worse. Sorafenib is approved in renal cell cancer and hepatocellular carcinoma. Sorafenib has also has also been evaluated in unselected advanced patients with NSCLC both alone or with chemotherapy in the first-time treatment of patients . MK-2206, and AZD6244 are not FDA-approved or commercially available. At this time, they are only being used in research.

Up to 450 patients will take part in this multicenter study. Approximately 350 will be enrolled at MD Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 334 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer
• Actual Study Start Date: Jun 2, 2011
• Actual Primary Completion Date: Nov 30, 2020
• Actual Study Completion Date: Nov 30, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1 - Erlotinib Erlotinib 150 mg by mouth each day of a 28 day cycle.	Drug: Erlotinib; 150 mg by mouth each day of a 28 day cycle.; Other Names: OSI-774 Tarceva
Experimental: Group 2 - Erlotinib + MK-2206 Erlotinib 150 mg by mouth each day of a 28 day cycle. MK-2206 135 mg by mouth every week of a 28 day cycle.	Drug: Erlotinib; 150 mg by mouth daily of a 28 day cycle.; Other Names: OSI-774 Tarceva ; Drug: MK-2206; 135 mg by mouth every week of a 28 day cycle.
Experimental: Group 3 - AZD6244 + MK-2206 AZD6244 100 mg by mouth daily of a 28 day cycle. MK-2206 100 mg by mouth every week of a 28 day cycle.	Drug: AZD6244; 100 mg by mouth daily of a 28 day cycle.; Drug: MK-2206; 100 mg by mouth every week of a 28 day cycle.
Experimental: Group 4 - Sorafenib Sorafenib 400 mg by mouth twice a day for a 28 day cycle.	Drug: Sorafenib; 400 mg by mouth twice a day for a 28 day cycle.; Other Names: Nexavar BAY43-9006

Outcome Measures

Primary Outcome Measures

1. 8-Week Disease Control Rate (DCR) [8 weeks]

   Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Secondary Outcome Measures

1. Median Progression-free Survival [From the date of drug start to the earliest sign of disease progression or death]

   Progression-free survival was estimated by Kaplan-Meier method

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. The subject has a diagnosis of pathologically confirmed NSCLC by tumor biopsy and/or fine-needle aspiration.

2. The subject has a diagnosis of either advanced, incurable stage IIIB or stage IV NSCLC, and failed at least one front-line metastatic NSCLC chemotherapy regimen, or EGFR TKI. (Subjects who have failed adjuvant or locally advanced therapy within 6 months are also eligible to participate in the study).

3. The subject has measurable NSCLC (patients with active new disease growth in previously irradiated site are eligible).

4. The subject's ECOG performance status is </= 2 at study entry.

5. The subject has biopsy accessible tumor

6. The subject has adequate hematologic function as defined by an absolute neutrophil count (ANC) >/= 1,500/mm3, platelet count >/= 100,000/mm3, WBC >/= 3,000/ mm3, and hemoglobin >/= 9 g/dL.

7. The subject has adequate hepatic function as defined by a total bilirubin level </= 1.5 x the upper limit of normal (ULN) (bilirubin >/= 1.5 x ULN with known Gilbert's disease is allowed), and alkaline phosphatase, AST and ALT </= 2.5 x the upper limit of normal or </= 5.0 x ULN if liver metastases are present.

8. Serum creatinine clearance >50ml/min, either by Cockcroft-Gault formula or 24-hour urine collection analysis

9. If subject has brain metastasis, they must have been stable (treated and/or asymptomatic) and off steroids for at least 2 weeks.

10. The subject is >/=18 years of age.

11. The subject has signed informed consent.

12. The subject is eligible if disease free from a previously treated malignancy, other than a previous NSCLC, for greater than two years. Subject with a history of prior basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix are allowed.

13. Women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Childbearing potential will be defined as women who have had menses within the past 12 months, who have not had tubal ligation, hysterectomy or bilateral oophorectomy. Should a woman become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician immediately.

14. The subject, if a man, agrees to use effective contraception or abstinence while on study and for 90 days after last dose of study drug.

15. Subject is able to swallow capsules and has no surgical or anatomical condition that will preclude the patient from swallowing and absorbing oral medications on an ongoing basis.

Exclusion Criteria:

1. The subject has received prior chemotherapy, surgery, or radiotherapy within 3 weeks of initiating study drug, or 4 weeks for bevacizumab or investigational drug or 72 hours for erlotinib or the subject has not recovered (</= Grade 1) from side effects of the prior therapy (localized palliative radiotherapy within 2 weeks is allowed).

2. The subject has undergone prior thoracic or abdominal surgery within 30 days of study entry, excluding prior diagnostic biopsy.

3. The subject has cardiac conditions as follows: uncontrolled hypertension BP > 140/90 despite optimal therapy, uncontrolled angina, ventricular arrhythmias, or congestive heart failure New York Heart Association Class II or above, baseline LVEF </= 50%, prior or current cardiomyopathy, atrial fibrillation with heart rate >100 bpm, unstable ischaemic heart disease (MI within 6 months prior to starting treatment, or angina requiring use of nitrates more than once weekly).

4. The subject has neuropathy >/= grade 2

5. The subject is pregnant (confirmed by serum b-HCG if applicable) or is breastfeeding. In the event of inconclusive pregnancy test results, the investigator will have final determination of pregnancy status.

6. Subjects will be excluded for other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study (i.e., uncontrolled diabetes, severe infection requiring active treatment, severe malnutrition, chronic severe liver or renal disease).

7. Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption

8. Subjects with poorly controlled diabetes (HbA1c >8%) are excluded.

9. Subjects whose tumor harbors the EML4-ALK fusion gene are excluded unless the patient has failed treatment with Anaplastic Lymphoma Kinase (ALK) inhibitor.

10. Subjects are excluded if they have QTc prolongation >450 msec (Bazett's Formula) for males or >470 ms for females on screening or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) including heart failure that meets New York Heart Association (NYHA) class II or above or require use of a concomitant medication that can prolong the QT interval.

11. Subjects who have abnormal K+ or Mg++ levels will be excluded if these levels cannot be corrected to within normal range with adequate supportive treatment prior to study drug initiation.

12. Subjects whose tumor harbors an EGFR mutation are excluded unless the subject failed treatment with EGFR TKIs in which case the subject can be randomized to Arms 2, 3, and

14. Drug Specific Eligibility Criteria based on Treatment Arms- Subjects are excluded from the erlotinib monotherapy arm if they have progressed on prior EGFR TKI therapy; from the AKT inhibitor arm(s) if they have received prior AKT inhibitor therapy; from the MEK inhibitor arm if they have received prior MEK inhibitor therapy; and from Sorafenib arm if they have previously received the drug or have prior history of clinically significant hemoptysis or bleeding diathesis as per principal investigator judgment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale Universtiy	New Haven	Connecticut	United States	06520
2	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• Merck Sharp & Dohme LLC
• National Cancer Institute (NCI)
• GlaxoSmithKline
• Novartis

Investigators

• Principal Investigator: Marcelo V. Negrao, MD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 8, 2019

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT01248247
• Other Study ID Numbers: 2009-0360; P01 CA148133; NCI-2011-01104
• First Posted: Nov 25, 2010
• Last Update Posted: Jan 12, 2022
• Last Verified: Dec 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by M.D. Anderson Cancer Center: Non small cell lung cancer; Biopsy accessible tumor; Stage IIIB non small cell lung cancer; Stage IV non small cell lung cancer
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Erlotinib Hydrochloride; Sorafenib

Study Results

Participant Flow

Recruitment Details	Patients with pretreated NSCLC who agreed to a baseline tumor biopsy, who had ECOG P of 0 to 2, and who had multiple prior lines of therapy and stable or treated brain metastases were enrolled. Patients were excluded if their tumor harbored EGFR sensitizing mutations or ALK gene fusions, and they were erlotinib or crizotinib na¨ıve.
Pre-assignment Detail	Total of 334 participants consented, 134 participants did not receive treatment a majority due to screen failures and others due to participants withdrew consent(s) and or progressed prior to treatment starting.

Arm/Group Title	Arm 1 - Erlotinib	Arm 2 - Erlotinib + MK-2206	Arm 3 - AZD6244 + MK-2206	Arm 4 - Sorafenib
Arm/Group Description	Erlotinib 150 mg by mouth each day of a 28 day cycle.	Erlotinib 150 mg by mouth each day of a 28 day cycle. MK-2206 135 mg by mouth every week of a 28 day cycle.	AZD6244 100 mg by mouth daily of a 28 day cycle. MK-2206 100 mg by mouth every week of a 28 day cycle.	Sorafenib 400 mg by mouth twice a day for a 28 day cycle.
Period Title: Overall Study
STARTED	22	42	75	61
COMPLETED	0	0	0	0
NOT COMPLETED	22	42	75	61

Baseline Characteristics

Arm/Group Title	Arm 1 - Erlotinib	Arm 2 - Erlotinib + MK-2206	Arm 3 - AZD6244 + MK-2206	Arm 4 - Sorafenib	Total
Arm/Group Description	Erlotinib 150 mg by mouth each day of a 28 day cycle.	Erlotinib 150 mg by mouth each day of a 28 day cycle. MK-2206 135 mg by mouth every week of a 28 day cycle.	AZD6244 100 mg by mouth daily of a 28 day cycle. MK-2206 100 mg by mouth every week of a 28 day cycle.	Sorafenib 400 mg by mouth twice a day for a 28 day cycle.	Total of all reporting groups
Overall Participants	22	42	75	61	200
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61	62	61	62	61
Age, Customized (Count of Participants)
<=49 years	2 9.1%	2 4.8%	6 8%	7 11.5%	17 8.5%
Between 50 and 59 years	8 36.4%	16 38.1%	27 36%	19 31.1%	70 35%
Between 60 and 69 years	10 45.5%	12 28.6%	29 38.7%	24 39.3%	75 37.5%
>=70 years	2 9.1%	12 28.6%	13 17.3%	11 18%	38 19%
Sex: Female, Male (Count of Participants)
Female	10 45.5%	15 35.7%	49 65.3%	32 52.5%	106 53%
Male	12 54.5%	27 64.3%	26 34.7%	29 47.5%	94 47%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 13.6%	1 2.4%	3 4%	7 11.5%	14 7%
Not Hispanic or Latino	19 86.4%	41 97.6%	72 96%	54 88.5%	186 93%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	1 1.6%	1 0.5%
Asian	1 4.5%	0 0%	2 2.7%	1 1.6%	4 2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	3 13.6%	2 4.8%	6 8%	8 13.1%	19 9.5%
White	18 81.8%	40 95.2%	67 89.3%	51 83.6%	176 88%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	22 100%	42 100%	75 100%	61 100%	200 100%
KRAS mut+ (Count of Participants)
No	16 72.7%	34 81%	53 70.7%	43 70.5%	146 73%
Yes	6 27.3%	8 19%	22 29.3%	18 29.5%	54 27%

Outcome Measures

1. Primary Outcome

Title	8-Week Disease Control Rate (DCR)
Description	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

12 participants were inevaluable and 2 participants were not applicable.

Arm/Group Title	Arm 1 - Erlotinib	Arm 2 - Erlotinib + MK-2206	Arm 3 - AZD6244 + MK-2206	Arm 4 - Sorafenib
Arm/Group Description	Erlotinib 150 mg by mouth each day of a 28 day cycle.	Erlotinib 150 mg by mouth each day of a 28 day cycle. MK-2206 135 mg by mouth every week of a 28 day cycle.	AZD6244 100 mg by mouth daily of a 28 day cycle. MK-2206 100 mg by mouth every week of a 28 day cycle.	Sorafenib 400 mg by mouth twice a day for a 28 day cycle.
Measure Participants	19	36	70	61
Partial Response	0 0%	0 0%	3 4%	3 4.9%
Stable Disease	6 27.3%	18 42.9%	34 45.3%	25 41%
Progressive Disease	13 59.1%	18 42.9%	33 44%	33 54.1%

2. Secondary Outcome

Title	Median Progression-free Survival
Description	Progression-free survival was estimated by Kaplan-Meier method
Time Frame	From the date of drug start to the earliest sign of disease progression or death

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 - Erlotinib	Arm 2 - Erlotinib + MK-2206	Arm 3 - AZD6244 + MK-2206	Arm 4 - Sorafenib
Arm/Group Description	Erlotinib 150 mg by mouth each day of a 28 day cycle.	Erlotinib 150 mg by mouth each day of a 28 day cycle. MK-2206 135 mg by mouth every week of a 28 day cycle.	AZD6244 100 mg by mouth daily of a 28 day cycle. MK-2206 100 mg by mouth every week of a 28 day cycle.	Sorafenib 400 mg by mouth twice a day for a 28 day cycle.
Measure Participants	22	42	75	61
Median (95% Confidence Interval) [months]	1.8	2.5	2.2	2.1

Adverse Events

Time Frame	From the first dose through 30 days after the last dose of study medication, up to 3 years
Arm/Group Title	Arm 1 - Erlotinib		Arm 2 - Erlotinib + MK-2206		Arm 3 - AZD6244 + MK-2206		Arm 4 - Sorafenib
Arm/Group Description	Erlotinib 150 mg by mouth each day of a 28 day cycle.		Erlotinib 150 mg by mouth each day of a 28 day cycle. MK-2206 135 mg by mouth every week of a 28 day cycle.		AZD6244 100 mg by mouth daily of a 28 day cycle. MK-2206 100 mg by mouth every week of a 28 day cycle.		Sorafenib 400 mg by mouth twice a day for a 28 day cycle.
All Cause Mortality
	Arm 1 - Erlotinib		Arm 2 - Erlotinib + MK-2206		Arm 3 - AZD6244 + MK-2206		Arm 4 - Sorafenib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/22 (86.4%)		36/42 (85.7%)		65/75 (86.7%)		51/61 (83.6%)
Serious Adverse Events
	Arm 1 - Erlotinib		Arm 2 - Erlotinib + MK-2206		Arm 3 - AZD6244 + MK-2206		Arm 4 - Sorafenib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/22 (13.6%)		13/42 (31%)		29/75 (38.7%)		24/61 (39.3%)
Blood and lymphatic system disorders
Anemia	0/22 (0%)		0/42 (0%)		0/75 (0%)		1/61 (1.6%)	1
Thrombotic thrombocytopenic purpura	0/22 (0%)		0/42 (0%)		0/75 (0%)		1/61 (1.6%)	1
Cardiac disorders
Cardiac arrest	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	0/61 (0%)	1
Chest pain - cardiac	0/22 (0%)		0/42 (0%)		0/75 (0%)		1/61 (1.6%)	1
Myocardial infarction	0/22 (0%)		1/42 (2.4%)	1	0/75 (0%)	1	0/61 (0%)	1
Pericardial effusion	0/22 (0%)		0/42 (0%)		0/75 (0%)		1/61 (1.6%)
Gastrointestinal disorders
Abdominal pain	0/22 (0%)		1/42 (2.4%)	1	0/75 (0%)	1	1/61 (1.6%)	1
Colitis	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	0/61 (0%)	0
Colonic perforation	0/22 (0%)		0/42 (0%)		0/75 (0%)		1/61 (1.6%)	1
Diarrhea	0/22 (0%)		2/42 (4.8%)	2	0/75 (0%)	2	1/61 (1.6%)	1
Dysphagia	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	1/61 (1.6%)	1
Esophageal hemorrhage	0/22 (0%)		0/42 (0%)		0/75 (0%)		1/61 (1.6%)	1
Esophageal stenosis	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	0/61 (0%)	1
Lower gastrointestinal hemorrhage	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	0/61 (0%)	1
Mucositis oral	0/22 (0%)		1/42 (2.4%)	1	0/75 (0%)	1	0/61 (0%)	1
Nausea	0/22 (0%)		1/42 (2.4%)	1	0/75 (0%)	1	1/61 (1.6%)	1
Pancreatitis	0/22 (0%)		1/42 (2.4%)	1	1/75 (1.3%)	1	0/61 (0%)	1
Vomiting	0/22 (0%)		2/42 (4.8%)	2	1/75 (1.3%)	1	0/61 (0%)	0
General disorders
Fatigue	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	0/61 (0%)	1
Fever	0/22 (0%)		2/42 (4.8%)	2	0/75 (0%)	2	0/61 (0%)	2
Multi-organ failure	1/22 (4.5%)	1	0/42 (0%)	1	0/75 (0%)	1	0/61 (0%)	1
Pain	0/22 (0%)		1/42 (2.4%)	1	1/75 (1.3%)	1	0/61 (0%)	1
Infections and infestations
Kidney infection	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	0/61 (0%)	1
Lung infection	1/22 (4.5%)	1	0/42 (0%)	1	3/75 (4%)	3	3/61 (4.9%)	4
Pancreas infection	0/22 (0%)		0/42 (0%)		0/75 (0%)		1/61 (1.6%)	1
Skin infection	0/22 (0%)		1/42 (2.4%)	1	0/75 (0%)	1	0/61 (0%)	1
Upper respiratory infection	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	0/61 (0%)	1
Urinary tract infection	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	1/61 (1.6%)	1
Injury, poisoning and procedural complications
Fall	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	0/61 (0%)	1
Fracture	0/22 (0%)		1/42 (2.4%)	1	1/75 (1.3%)	1	0/61 (0%)	1
Investigations
Investigations - Other, specify	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	0/61 (0%)	1
Metabolism and nutrition disorders
Anorexia	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	0/61 (0%)	0
Dehydration	0/22 (0%)		0/42 (0%)		0/75 (0%)		1/61 (1.6%)	1
Hypercalcemia	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	0/61 (0%)	1
Hyperglycemia	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	0/61 (0%)	1
Musculoskeletal and connective tissue disorders
Back pain	0/22 (0%)		1/42 (2.4%)	1	0/75 (0%)	0	4/61 (6.6%)	5
Buttock pain	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	0/61 (0%)	1
Flank pain	0/22 (0%)		1/42 (2.4%)	1	0/75 (0%)	1	0/61 (0%)	1
Generalized muscle weakness	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	0/61 (0%)	1
Pain in extremity	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	0/61 (0%)	1
Nervous system disorders
Seizure	0/22 (0%)		0/42 (0%)		0/75 (0%)		1/61 (1.6%)	1
Stroke	0/22 (0%)		0/42 (0%)		0/75 (0%)		1/61 (1.6%)	2
Renal and urinary disorders
Acute kidney injury	0/22 (0%)		0/42 (0%)		3/75 (4%)		0/61 (0%)
Hematuria	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	0/61 (0%)	1
Renal colic	0/22 (0%)		1/42 (2.4%)	1	0/75 (0%)	1	0/61 (0%)	1
Reproductive system and breast disorders
Dyspnea	1/22 (4.5%)	1	1/42 (2.4%)	1	7/75 (9.3%)	11	5/61 (8.2%)	5
Respiratory, thoracic and mediastinal disorders
Aspiration	0/22 (0%)		1/42 (2.4%)	1	0/75 (0%)	0	1/61 (1.6%)	1
Hypoxia	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	0/61 (0%)	1
Pleural effusion	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	4/61 (6.6%)	4
Pneumonitis	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	0/61 (0%)	1
Pneumothorax	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	1/61 (1.6%)	1
Respiratory failure	0/22 (0%)		2/42 (4.8%)	2	3/75 (4%)	3	0/61 (0%)	3
Respiratory, thoracic and mediastinal disorders - Other, specify	0/22 (0%)		0/42 (0%)		0/75 (0%)		1/61 (1.6%)
Skin and subcutaneous tissue disorders
Periorbital edema	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	0/61 (0%)	1
Rash maculo-papular	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	1	0/61 (0%)	1
Surgical and medical procedures
Surgical and medical procedures - Other, specify	0/22 (0%)		0/42 (0%)		1/75 (1.3%)	2	1/61 (1.6%)	1
Vascular disorders
Hypertension	0/22 (0%)		0/42 (0%)		0/75 (0%)		1/61 (1.6%)	1
Thromboembolic event	0/22 (0%)		0/42 (0%)		4/75 (5.3%)	5	1/61 (1.6%)	1
Other (Not Including Serious) Adverse Events
	Arm 1 - Erlotinib		Arm 2 - Erlotinib + MK-2206		Arm 3 - AZD6244 + MK-2206		Arm 4 - Sorafenib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/22 (95.5%)		42/42 (100%)		75/75 (100%)		61/61 (100%)
Blood and lymphatic system disorders
Anemia	0/22 (0%)		2/42 (4.8%)		2/75 (2.7%)		7/61 (11.5%)
Gastrointestinal disorders
Diarrhea	8/22 (36.4%)		24/42 (57.1%)		26/75 (34.7%)		16/61 (26.2%)
Nausea	7/22 (31.8%)		13/42 (31%)		25/75 (33.3%)		12/61 (19.7%)
Vomiting	5/22 (22.7%)		10/42 (23.8%)		27/75 (36%)		14/61 (23%)
Oral mucositis	3/22 (13.6%)		13/42 (31%)		14/75 (18.7%)		10/61 (16.4%)
Dry mouth	1/22 (4.5%)		6/42 (14.3%)		6/75 (8%)		5/61 (8.2%)
General disorders
Fatigue	2/22 (9.1%)		15/42 (35.7%)		31/75 (41.3%)		26/61 (42.6%)
Investigations
Increased AST	5/22 (22.7%)		5/42 (11.9%)		29/75 (38.7%)		7/61 (11.5%)
Increased alkaline phosphatase	2/22 (9.1%)		10/42 (23.8%)		17/75 (22.7%)		22/61 (36.1%)
Weight loss	3/22 (13.6%)		11/42 (26.2%)		2/75 (2.7%)		5/61 (8.2%)
Increased ALT	0/22 (0%)		5/42 (11.9%)		22/75 (29.3%)		9/61 (14.8%)
Increased blood bilirubin	5/22 (22.7%)		2/42 (4.8%)		1/75 (1.3%)		9/61 (14.8%)
Increased creatinine	0/22 (0%)		5/42 (11.9%)		2/75 (2.7%)		8/61 (13.1%)
Metabolism and nutrition disorders
Anorexia	6/22 (27.3%)		16/42 (38.1%)		9/75 (12%)		15/61 (24.6%)
Hyperglycemia	2/22 (9.1%)		11/42 (26.2%)		24/75 (32%)		4/61 (6.6%)
Hyponatremia	1/22 (4.5%)		3/42 (7.1%)		0/75 (0%)		7/61 (11.5%)
Hypoalbuminemia	1/22 (4.5%)		1/42 (2.4%)		1/75 (1.3%)		0/61 (0%)
Hypophosphatemia	0/22 (0%)		0/42 (0%)		0/75 (0%)		4/61 (6.6%)
Nervous system disorders
Dysgeusia	1/22 (4.5%)		5/42 (11.9%)		3/75 (4%)		2/61 (3.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/22 (4.5%)		2/42 (4.8%)		8/75 (10.7%)		15/61 (24.6%)
Hoarseness	0/22 (0%)		0/42 (0%)		1/75 (1.3%)		4/61 (6.6%)
Epistaxis	3/22 (13.6%)		0/42 (0%)		1/75 (1.3%)		8/61 (13.1%)
Skin and subcutaneous tissue disorders
Rash Maculopapular	3/22 (13.6%)		14/42 (33.3%)		29/75 (38.7%)		24/61 (39.3%)
Rash Acneiform	11/22 (50%)		18/42 (42.9%)		29/75 (38.7%)		3/61 (4.9%)
Dry skin	7/22 (31.8%)		12/42 (28.6%)		13/75 (17.3%)		18/61 (29.5%)
Pruritus	1/22 (4.5%)		4/42 (9.5%)		8/75 (10.7%)		5/61 (8.2%)
Other skin and subcutaneous tissue disorders, specify	3/22 (13.6%)		3/42 (7.1%)		8/75 (10.7%)		7/61 (11.5%)
Palmar-plantar erythrodysesthesia syndrome	1/22 (4.5%)		0/42 (0%)		1/75 (1.3%)		3/61 (4.9%)
Alopecia	0/22 (0%)		1/42 (2.4%)		5/75 (6.7%)		10/61 (16.4%)
Vascular disorders
Hypertension	0/22 (0%)		1/42 (2.4%)		2/75 (2.7%)		7/61 (11.5%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.