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MK-2206 and AZD6244 in Patients With Advanced Colorectal Carcinoma

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ClinicalTrials.gov Identifier: NCT01333475
Recruitment Status : Completed
First Posted : April 12, 2011
Results First Posted : December 4, 2014
Last Update Posted : September 30, 2015
Sponsor:
Information provided by (Responsible Party):
Shivaani Kummar, M.D., National Institutes of Health Clinical Center (CC)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Colorectal Neoplasms
Intervention Drug: MK-2206 + AZD6244
Enrollment 21
Recruitment Details  
Pre-assignment Details

Because dual target evaluation of >70% was not observed in the tumor biopsies from any of the participants evaluated, no participants were enrolled to Cohort C to evaluate target recovery.

TAC1 and TAC1A -Since all patients received both drugs, each of the TACs (Treatment Assignment Code) reflect the dose level.

Arm/Group Title TAC1 TAC1A
Hide Arm/Group Description

Cycle = 28 days:MK-2206:90 mg PO days 1, 8, 15, and 22 AZD6244 Hydrogen sulfate: 75 mg PO QD

MK-2206 + AZD6244: MK-2206 and AZD6244 hydrogen sulfate are selective inhibitors of human AKT and MEK, respectively, with preclinical and clinical anti-tumor activity as single agents and in combination with a variety of drugs. Combination treatment in mouse cancer models harboring mutations in both the PI3K and RAS pathways was more potent compared to either agent used alone, and resulted in substantial tumor inhibition, including tumor regression.

Cycle = 28 days:MK-2206:135 mg PO days 1, 8, 15, and 22 AZD6244 Hydrogen sulfate: 100 mg PO QD

MK-2206 + AZD6244: MK-2206 and AZD6244 hydrogen sulfate are selective inhibitors of human AKT and MEK, respectively, with preclinical and clinical anti-tumor activity as single agents and in combination with a variety of drugs. Combination treatment in mouse cancer models harboring mutations in both the PI3K and RAS pathways was more potent compared to either agent used alone, and resulted in substantial tumor inhibition, including tumor regression.

Period Title: Overall Study
Started 12 9
Completed 10 6
Not Completed 2 3
Reason Not Completed
pt withdrew-need emergent radiation trmt             1             0
Toxicity             1             3
Arm/Group Title TAC1 TAC1A Total
Hide Arm/Group Description

Cycle = 28 days:MK-2206:90 mg PO days 1, 8, 15, and 22 AZD6244 Hydrogen sulfate: 75 mg PO QD

MK-2206 + AZD6244: MK-2206 and AZD6244 hydrogen sulfate are selective inhibitors of human AKT and MEK, respectively, with preclinical and clinical anti-tumor activity as single agents and in combination with a variety of drugs. Combination treatment in mouse cancer models harboring mutations in both the PI3K and RAS pathways was more potent compared to either agent used alone, and resulted in substantial tumor inhibition, including tumor regression.

Cycle = 28 days:MK-2206: 135 mg PO days 1, 8, 15, and 22 AZD6244 Hydrogen sulfate: 100 mg PO QD

MK-2206 + AZD6244: MK-2206 and AZD6244 hydrogen sulfate are selective inhibitors of human AKT and MEK, respectively, with preclinical and clinical anti-tumor activity as single agents and in combination with a variety of drugs. Combination treatment in mouse cancer models harboring mutations in both the PI3K and RAS pathways was more potent compared to either agent used alone, and resulted in substantial tumor inhibition, including tumor regression.

Total of all reporting groups
Overall Number of Baseline Participants 12 9 21
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 12 participants 9 participants 21 participants
54.1  (16.4) 53.8  (9.3) 54.0  (13.7)
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 9 participants 21 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
10
  83.3%
8
  88.9%
18
  85.7%
>=65 years
2
  16.7%
1
  11.1%
3
  14.3%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 9 participants 21 participants
Female
6
  50.0%
1
  11.1%
7
  33.3%
Male
6
  50.0%
8
  88.9%
14
  66.7%
Race (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 9 participants 21 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
1
   8.3%
0
   0.0%
1
   4.8%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
1
   8.3%
2
  22.2%
3
  14.3%
White
10
  83.3%
6
  66.7%
16
  76.2%
More than one race
0
   0.0%
1
  11.1%
1
   4.8%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Description: One participant selected White and Asian for Race, thus the category "More than one race" was selected. Six participants versus seven is noted in the "White" category and no participants is noted in the "Asian" category.
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 9 participants 21 participants
Hispanic or Latino
0
   0.0%
1
  11.1%
1
   4.8%
Not Hispanic or Latino
12
 100.0%
8
  88.9%
20
  95.2%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 12 participants 9 participants 21 participants
12 9 21
1.Primary Outcome
Title pERK and pAKT Levels in Tumor Biopsies on C1D1 and C1D22 Post-administration of the Combination of AZD6244 Hydrogen Sulfate and MK-2206 in Participants With Advanced Colorectal Cancer
Hide Description A predetermined target inhibition reduction of 70% of both pERK and pAKT was deemed significant, thus tumor biopsies were performed at C1D1 or C1D22 post administration and evaluated using quantitative chemiluminescence immunoassay to measure pERK and pAKT levels in human tissue.
Time Frame C1D1 and C1D22 post administration of the combination of AZD6244 hydrogen sulfate and MK-2206
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title TAC1 TAC1A
Hide Arm/Group Description:

Cycle = 28 days:MK-2206:90 mg PO days 1, 8, 15, and 22 AZD6244 Hydrogen sulfate: 75 mg PO QD

MK-2206 + AZD6244: MK-2206 and AZD6244 hydrogen sulfate are selective inhibitors of human AKT and MEK, respectively, with preclinical and clinical anti-tumor activity as single agents and in combination with a variety of drugs. Combination treatment in mouse cancer models harboring mutations in both the PI3K and RAS pathways was more potent compared to either agent used alone, and resulted in substantial tumor inhibition, including tumor regression.

Cycle = 28 days:MK-2206: 135mg PO days 1, 8, 15, and 22 AZD6244 Hydrogen sulfate: 100 mg PO QD

MK-2206 + AZD6244: MK-2206 and AZD6244 hydrogen sulfate are selective inhibitors of human AKT and MEK, respectively, with preclinical and clinical anti-tumor activity as single agents and in combination with a variety of drugs. Combination treatment in mouse cancer models harboring mutations in both the PI3K and RAS pathways was more potent compared to either agent used alone, and resulted in substantial tumor inhibition, including tumor regression.

Overall Number of Participants Analyzed 10 6
Mean (Full Range)
Unit of Measure: pg/ µg of protein
pAKT Baseline C1D1
4.86
(1.89 to 7.41)
0
(0 to 0)
pAKT post administration C1D1
2.20
(1.44 to 3.44)
NA [1] 
(NA to NA)
pAKT Baseline C1D22
NA [1] 
(NA to NA)
4.22
(1.56 to 7.64)
pAKT Post administration C1D22
NA [1] 
(NA to NA)
2.91
(1.27 to 7.3)
pERK Baseline C1D1
5.06
(1.56 to 12.26)
NA [1] 
(NA to NA)
pERK post administration C1D1
2.77
(1.56 to 4.93)
NA [1] 
(NA to NA)
pERK Baseline C1D22
NA [1] 
(NA to NA)
3.97
(1.56 to 7.19)
pERK Post administration C1D22
NA [1] 
(NA to NA)
3.5
(1.56 to 6.82)
[1]
N/A values identify levels that were not investigated - no participants were enrolled.
2.Secondary Outcome
Title Number of Participants With Adverse Events
Hide Description Here is the number of participants with adverse events. For the detailed list of adverse events, see the adverse event module.
Time Frame 29 months, 23 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title TAC1 TAC1A
Hide Arm/Group Description:

Cycle = 28 days:MK-2206:90 mg PO days 1, 8, 15, and 22 AZD6244 Hydrogen sulfate: 75 mg PO QD

MK-2206 + AZD6244: MK-2206 and AZD6244 hydrogen sulfate are selective inhibitors of human AKT and MEK, respectively, with preclinical and clinical anti-tumor activity as single agents and in combination with a variety of drugs. Combination treatment in mouse cancer models harboring mutations in both the PI3K and RAS pathways was more potent compared to either agent used alone, and resulted in substantial tumor inhibition, including tumor regression.

Cycle = 28 days:MK-2206: 135 mg PO days 1, 8, 15, and 22 AZD6244 Hydrogen sulfate: 100 mg PO QD

MK-2206 + AZD6244: MK-2206 and AZD6244 hydrogen sulfate are selective inhibitors of human AKT and MEK, respectively, with preclinical and clinical anti-tumor activity as single agents and in combination with a variety of drugs. Combination treatment in mouse cancer models harboring mutations in both the PI3K and RAS pathways was more potent compared to either agent used alone, and resulted in substantial tumor inhibition, including tumor regression.

Overall Number of Participants Analyzed 12 9
Measure Type: Number
Unit of Measure: participants
12 8
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title TAC1 TAC1A
Hide Arm/Group Description

Cycle = 28 days:MK-2206:90 mg PO days 1, 8, 15, and 22 AZD6244 Hydrogen sulfate: 75 mg PO QD

MK-2206 + AZD6244: MK-2206 and AZD6244 hydrogen sulfate are selective inhibitors of human AKT and MEK, respectively, with preclinical and clinical anti-tumor activity as single agents and in combination with a variety of drugs. Combination treatment in mouse cancer models harboring mutations in both the PI3K and RAS pathways was more potent compared to either agent used alone, and resulted in substantial tumor inhibition, including tumor regression.

Cycle = 28 days:MK-2206: 135 mg PO days 1, 8, 15, and 22 AZD6244 Hydrogen sulfate: 100 mg PO QD

MK-2206 + AZD6244: MK-2206 and AZD6244 hydrogen sulfate are selective inhibitors of human AKT and MEK, respectively, with preclinical and clinical anti-tumor activity as single agents and in combination with a variety of drugs. Combination treatment in mouse cancer models harboring mutations in both the PI3K and RAS pathways was more potent compared to either agent used alone, and resulted in substantial tumor inhibition, including tumor regression.

All-Cause Mortality
TAC1 TAC1A
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
TAC1 TAC1A
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5/12 (41.67%)      6/9 (66.67%)    
Gastrointestinal disorders     
Nausea  1  0/12 (0.00%)  0 1/9 (11.11%)  1
Infections and infestations     
Biliary tract infection  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Investigations     
Aspartate aminotransferase increased  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Blood bilirubin increased  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Metabolism and nutrition disorders     
Anorexia  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Back pain  1  0/12 (0.00%)  0 1/9 (11.11%)  1
Bone pain  1  0/12 (0.00%)  0 1/9 (11.11%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify  1 [1]  3/12 (25.00%)  3 0/9 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify  1 [2]  0/12 (0.00%)  0 3/9 (33.33%)  3
Renal and urinary disorders     
Urinary tract pain  1  0/12 (0.00%)  0 1/9 (11.11%)  1
Urinary urgency  1  0/12 (0.00%)  0 1/9 (11.11%)  1
Respiratory, thoracic and mediastinal disorders     
Aspiration  1  0/12 (0.00%)  0 1/9 (11.11%)  1
Surgical and medical procedures     
Surgical and medical procedures - Other, specify  1 [3]  0/12 (0.00%)  0 1/9 (11.11%)  1
Vascular disorders     
Thromboembolic event  1  0/12 (0.00%)  0 1/9 (11.11%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE (4.0)
[1]
progressive disease
[2]
progressive disease; disease progression
[3]
tumor resection
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
TAC1 TAC1A
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   12/12 (100.00%)      8/9 (88.89%)    
Blood and lymphatic system disorders     
Anemia  1  6/12 (50.00%)  11 4/9 (44.44%)  11
Cardiac disorders     
Palpitations  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Sinus bradycardia  1  3/12 (25.00%)  3 1/9 (11.11%)  2
Sinus tachycardia  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Eye disorders     
Blurred vision  1  1/12 (8.33%)  3 0/9 (0.00%)  0
Floaters  1  0/12 (0.00%)  0 1/9 (11.11%)  2
Retinal detachment  1  4/12 (33.33%)  4 0/9 (0.00%)  0
Watering eyes  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Gastrointestinal disorders     
Abdominal distension  1  2/12 (16.67%)  2 0/9 (0.00%)  0
Abdominal pain  1  2/12 (16.67%)  3 1/9 (11.11%)  1
Bloating  1  2/12 (16.67%)  2 1/9 (11.11%)  1
Constipation  1  1/12 (8.33%)  1 2/9 (22.22%)  3
Diarrhea  1  4/12 (33.33%)  9 4/9 (44.44%)  11
Dry mouth  1  0/12 (0.00%)  0 3/9 (33.33%)  3
Dyspepsia  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Flatulence  1  1/12 (8.33%)  1 1/9 (11.11%)  1
Gastroesophageal reflux disease  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Mucositis oral  1  2/12 (16.67%)  2 1/9 (11.11%)  1
Nausea  1  7/12 (58.33%)  13 5/9 (55.56%)  14
Vomiting  1  5/12 (41.67%)  10 4/9 (44.44%)  11
General disorders     
Chills  1  0/12 (0.00%)  0 2/9 (22.22%)  4
Edema face  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Edema limbs  1  3/12 (25.00%)  3 1/9 (11.11%)  3
Edema trunk  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Fatigue  1  7/12 (58.33%)  9 2/9 (22.22%)  2
Fever  1  1/12 (8.33%)  1 2/9 (22.22%)  3
Flu like symptoms  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Non-cardiac chest pain  1  2/12 (16.67%)  2 0/9 (0.00%)  0
Pain  1  2/12 (16.67%)  2 1/9 (11.11%)  1
Immune system disorders     
Allergic rhinitis  1  0/12 (0.00%)  0 1/9 (11.11%)  1
Infections and infestations     
Infections and infestations - Other, specify  1 [1]  1/12 (8.33%)  1 0/9 (0.00%)  0
Infections and infestations - Other, specify  1 [2]  0/12 (0.00%)  0 1/9 (11.11%)  1
Skin infection  1  0/12 (0.00%)  0 1/9 (11.11%)  1
Urinary tract infection  1  1/12 (8.33%)  1 2/9 (22.22%)  3
Injury, poisoning and procedural complications     
Fall  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Injury, poisoning and procedural complications - Other, specify  1 [3]  0/12 (0.00%)  0 1/9 (11.11%)  1
Investigations     
Activated partial thromboplastin time prolonged  1  2/12 (16.67%)  2 3/9 (33.33%)  4
Alanine aminotransferase increased  1  7/12 (58.33%)  16 6/9 (66.67%)  11
Alkaline phosphatase increased  1  7/12 (58.33%)  16 6/9 (66.67%)  9
Aspartate aminotransferase increased  1  10/12 (83.33%)  27 5/9 (55.56%)  14
Blood bilirubin increased  1  5/12 (41.67%)  9 1/9 (11.11%)  1
CPK increased  1  4/12 (33.33%)  6 1/9 (11.11%)  1
Creatinine increased  1  2/12 (16.67%)  5 0/9 (0.00%)  0
Lymphocyte count decreased  1  7/12 (58.33%)  11 6/9 (66.67%)  11
Lymphocyte count increased  1  1/12 (8.33%)  3 0/9 (0.00%)  0
Neutrophil count decreased  1  0/12 (0.00%)  0 1/9 (11.11%)  2
Platelet count decreased  1  3/12 (25.00%)  4 3/9 (33.33%)  6
Weight loss  1  0/12 (0.00%)  0 1/9 (11.11%)  2
White blood cell decreased  1  1/12 (8.33%)  1 2/9 (22.22%)  7
Metabolism and nutrition disorders     
Anorexia  1  3/12 (25.00%)  5 3/9 (33.33%)  3
Dehydration  1  2/12 (16.67%)  2 1/9 (11.11%)  3
Hypercalcemia  1  5/12 (41.67%)  10 6/9 (66.67%)  7
Hyperglycemia  1  2/12 (16.67%)  15 3/9 (33.33%)  4
Hyperkalemia  1  2/12 (16.67%)  5 0/9 (0.00%)  0
Hypermagnesemia  1  1/12 (8.33%)  1 1/9 (11.11%)  2
Hyperuricemia  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Hypoalbuminemia  1  11/12 (91.67%)  24 6/9 (66.67%)  11
Hypocalcemia  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Hypokalemia  1  2/12 (16.67%)  3 0/9 (0.00%)  0
Hypomagnesemia  1  5/12 (41.67%)  11 2/9 (22.22%)  5
Hyponatremia  1  7/12 (58.33%)  9 4/9 (44.44%)  8
Hypophosphatemia  1  0/12 (0.00%)  0 1/9 (11.11%)  2
Musculoskeletal and connective tissue disorders     
Back pain  1  1/12 (8.33%)  2 1/9 (11.11%)  2
Bone pain  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Flank pain  1  1/12 (8.33%)  1 1/9 (11.11%)  1
Generalized muscle weakness  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Nervous system disorders     
Dizziness  1  2/12 (16.67%)  2 1/9 (11.11%)  2
Dysgeusia  1  0/12 (0.00%)  0 1/9 (11.11%)  1
Headache  1  1/12 (8.33%)  2 2/9 (22.22%)  3
Psychiatric disorders     
Anxiety  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Depression  1  1/12 (8.33%)  1 1/9 (11.11%)  1
Insomnia  1  1/12 (8.33%)  2 0/9 (0.00%)  0
Psychiatric disorders - Other, specify  1 [4]  1/12 (8.33%)  1 0/9 (0.00%)  0
Psychiatric disorders - Other, specify  1 [5]  0/12 (0.00%)  0 1/9 (11.11%)  2
Renal and urinary disorders     
Cystitis noninfective  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Hematuria  1  0/12 (0.00%)  0 1/9 (11.11%)  1
Proteinuria  1  1/12 (8.33%)  1 2/9 (22.22%)  2
Urinary tract pain  1  0/12 (0.00%)  0 1/9 (11.11%)  1
Respiratory, thoracic and mediastinal disorders     
Cough  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Dyspnea  1  2/12 (16.67%)  2 1/9 (11.11%)  1
Epistaxis  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Hiccups  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Hoarseness  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Nasal congestion  1  0/12 (0.00%)  0 1/9 (11.11%)  1
Pleural effusion  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Postnasal drip  1  0/12 (0.00%)  0 1/9 (11.11%)  1
Respiratory, thoracic and mediastinal disorders - Other, specify  1 [6]  0/12 (0.00%)  0 1/9 (11.11%)  1
Sore throat  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Wheezing  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Skin and subcutaneous tissue disorders     
Dry skin  1  1/12 (8.33%)  2 2/9 (22.22%)  3
Papulopustular rash  1  2/12 (16.67%)  2 0/9 (0.00%)  0
Periorbital edema  1  1/12 (8.33%)  1 0/9 (0.00%)  0
Pruritis  1  0/12 (0.00%)  0 2/9 (22.22%)  5
Rash acneiform  1  3/12 (25.00%)  3 6/9 (66.67%)  13
Rash maculo-papular  1  2/12 (16.67%)  3 3/9 (33.33%)  5
Vascular disorders     
Hypertension  1  10/12 (83.33%)  39 7/9 (77.78%)  22
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE (4.0)
[1]
infection limbs
[2]
small intestine
[3]
right small toe bruising/laceration
[4]
night dreams
[5]
vivid dreams
[6]
dry nose
Certain Agreements
Principal Investigators are NOT 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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Shivaani Kummar
Organization: National Cancer Institute
Phone: 301-435-0517
EMail: kummars@mail.nih.gov
Layout table for additonal information
Responsible Party: Shivaani Kummar, M.D., National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT01333475     History of Changes
Other Study ID Numbers: 110117
11-C-0117
First Submitted: April 9, 2011
First Posted: April 12, 2011
Results First Submitted: November 19, 2014
Results First Posted: December 4, 2014
Last Update Posted: September 30, 2015