A Study of the Safety and Activity of the MEK Inhibitor Given Together With the AKT Inhibitor to Patients With Multiple Myeloma or Solid Tumor Cancers

NCT01476137 | Completed Phase 1 DMC

• 1 other identifier: 115829
• Study Type: interventional
• Target: 335
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this study is to determine whether the MEK inhibitor and the AKT inhibitor can be given in combination and if the combination is effective treatment for patients with solid tumors, including breast cancer and endometrial cancer, and for patients with multiple myeloma.

Conditions

Cancer

Keywords

oncology; solid tumors; multiple myeloma; AKT inhibitor; MEK inhibitor

Outcome Measures

Primary Outcomes (4)

• Part 1: Safety and tolerability in first 4 weeks as determined by the number of patients with adverse events, serious adverse events, dose reductions or delays, withdrawals due to toxicities and changes in lab values and vital signs from baseline

  Adverse events, serious adverse events, dose reductions or delays, withdrawals due to toxicities and changes in laboratory values and vital signs

  Weekly during first four weeks.

• Part 2A: Number of patients whose disease responds to study drugs, as determined by Overall Response Rate (ORR)

  Defined as stringent complete response, complete response, very good partial response, or partial response, using the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma

  Every four weeks for up to one year.

• Part 2B: Number of patients whose disease responds to study drugs, as determined by Overall response rate (ORR)

  Defined as confirmed complete response or confirmed partial response rate, using Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1

  Until disease progression or for up to one year.

• Part 1: Safety and tolerability in continuation as determined by the number of patients with adverse events, serious adverse events, dose reductions or delays, withdrawals due to toxicities and changes in lab values and vital signs from baseline

  Adverse events, serious adverse events, dose reductions or delays, withdrawals due to toxicities and changes in laboratory values and vital signs

  Every four weeks for up to one year.

Secondary Outcomes (3)

• Part 1: Profile of pharmacokinetic parameters following repeat-dose administration of GSK1120212 and GSK2110183 in combination versus repeat-dose administration of monotherapy GSK2110183 and GSK1120212

  Day 15 and Day 29 at predose and 1h, 2h, 3h, 4h, 6h, 8h 11h, 18h and 24h postdose

• Part 2A: Number of patients whose disease responds to study drugs, as shown by PFS; duration of response; change from baseline measures in biomarkers in the PI3K/ATK and MAPK pathways; genetic alterations in PI3K/AKT/RAS/RAF pathway

  Every 4 weeks

• Part 2B: Number of patients whose disease responds to study drugs, as shown by PFS; duration of response; change from baseline measures in biomarkers in the PI3K/ATK and MAPK pathways; genetic alterations in PI3K/AKT/RAS/RAF pathway

  Every 8 weeks

Study Arms (10)

Part 2A and 2B: GSK1120212 + GSK2110183 Dose Combination 1

EXPERIMENTAL

One of two dose combination levels (GSK1120212+GSK2110183) based on data from Part 1 of the trial

Drug: GSK1120212; Drug: GSK2110183

Part 2A and 2B: GSK1120212 + GSK2110183 Dose Combination 2

EXPERIMENTAL

One of two dose combination levels (GSK1120212+GSK2110183) based on data from Part 1 of the trial

Drug: GSK1120212; Drug: GSK2110183

Part 1: Cohort 1

EXPERIMENTAL

GSK1120212 1.5mg + GSK2110183 50mg

Drug: GSK1120212; Drug: GSK2110183

Part 1: Cohort 2

EXPERIMENTAL

GSK1120212 1.5mg + GSK2110183 100mg

Drug: GSK1120212; Drug: GSK2110183

Part 1: Cohort 3a

EXPERIMENTAL

GSK1120212 2mg + GSK2110183 100mg

Drug: GSK1120212; Drug: GSK2110183

Part 1: Cohort 3b

EXPERIMENTAL

GSK1120212 1.5mg + GSK2110183 125mg

Drug: GSK1120212; Drug: GSK2110183

Part 1: Cohort 4a

EXPERIMENTAL

GSK1120212 2mg + GSK2110183 125mg

Drug: GSK1120212; Drug: GSK2110183

Part 2A: GSK1120212 2mg

EXPERIMENTAL

Maximum tolerated dose of GSK1120212 as determined in prior single-agent trials

Drug: GSK1120212

Part 2A; GSK2110183 125mg

EXPERIMENTAL

GSK2110183 125mg

Drug: GSK2110183

Part 2A: GSK2110183 MTD

EXPERIMENTAL

Maximum tolerated dose (MTD) as determined in ongoing single agent trial PKB115340

Drug: GSK2110183

Interventions

GSK1120212 DRUG

MEK inhibitor

Part 1: Cohort 1; Part 1: Cohort 2; Part 1: Cohort 3a; Part 1: Cohort 3b; Part 1: Cohort 4a; Part 2A and 2B: GSK1120212 + GSK2110183 Dose Combination 1; Part 2A and 2B: GSK1120212 + GSK2110183 Dose Combination 2; Part 2A: GSK1120212 2mg

GSK2110183 DRUG

AKT inhibitor

Part 1: Cohort 1; Part 1: Cohort 2; Part 1: Cohort 3a; Part 1: Cohort 3b; Part 1: Cohort 4a; Part 2A and 2B: GSK1120212 + GSK2110183 Dose Combination 1; Part 2A and 2B: GSK1120212 + GSK2110183 Dose Combination 2; Part 2A: GSK2110183 MTD; Part 2A; GSK2110183 125mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female, at least 18 years of age at the time of signing informed consent form and capable of giving written informed consent, which includes willingness to comply with the requirements and restrictions listed in the consent form.
• Histologically or cytologically confirmed diagnosis of a solid tumor malignancy with one of the following characteristics that is not responsive to standard therapies or for which there is no approved or curative therapy or for subjects which refuse standard therapy: breast cancer, colorectal cancer, pancreatic cancer, endometrial cancer, non-small cell lung cancer, ovarian cancer, melanoma, renal cell carcinoma, head and neck cancer, prostate cancer, gastric cancer, hepatocellular cancer, or bladder cancer.
• At Screening, archived tissue must be requested. If archived tissue is not available, a fresh biopsy is required.
• Subjects diagnosed previously with Type 2 diabetes must have been diagnosed at least 6 months prior to enrollment.
• All prior treatment-related toxicities must be less than or equal to Grade 1 according to NCI-CTCAE (version 4.0) at the time of treatment allocation, or are less than or equal to Grade 2 and stable for 4 weeks or longer at the time of screening evaluation.
• Adequate organ system function: absolute neutrophil count (ANC) greater than or equal to 1.5X10\^9/L, hemoglobin greater than or equal to 9g/dL, , platelets greater than or equal to 75X10\^9/L, PT/INR and PTT less than or equal to 1.5Xupper limit of normal (ULN); total bilirubin less than or equal to 1.5XULN, AST and ALT less than or equal to 2.5XULN, albumin greater than or equal to 2.5g/dL; creatinine less than 2.5mg/dL or calculated or 24-hour urine creatining clearance greater than or equal to 30mL/min; fasting serum glucose less than 126mg/dL (7mmol/L), HbA1C less than or equal to 8% and cardiac ejection fraction greater than or equal to the lower limit of normal (LLN) by echocardiography.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• All subjects enrolled in the serial PK cohorts must agree to serial PK sampling.
• Must agree to collection of samples for evaluation of circulating free DNA (cfDNA).
• Able to swallow and retain orally administered medication.
• Women of childbearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control. Additionally, women of childbearing potential must have a negative serum pregnancy test within 14 days prior to the first dose of study medication.
• As listed for Part 1 with the exception of criterion 2 which should be replaced with the following:
• Histologically confirmed diagnosis of secretory multiple myeloma (must have measurable M protein in serum or urine) with at least one of the following: serum M protein greater than or equal to 1g/dL, urine M protein greater than or equal to 200mg/24hours, serum Free Light Chain (FLC) assay- involved FLC level greater than or equal to 10mg/dL and an abnormal serum FLC ratio (\<0.26 or \>1.65), biopsy-proven plasmacytoma within 28 days of screening visit.
• Adequate organ system function, defined as ANC greater than or equal to 1X10\^9/L, hemoglobin greater than or equal to 8g/dL, platelets greater than or equal to 50X10\^9/L, PT/INR and PTT less than or equal to 1.5XULN, total bilirubin less than or equal to 1.5XULN, AST and ALT less than or equal to 2.5XULN, albumin greater than or equal to 2.5g/dL, creatinine less than or equal to 2.5mg/dL or calculated or 24-hour urine creatinine clearance greater than or equal to 30mL/min; fasting serum glucose less than 126mg/dL, HbA1C less than or equal to 8%, calcium less than or equal to 12.5mg/dL (3.126mmol/L), cardiac ejection fraction greater than or equal to LLN by echocardiography.
• Subjects with a history of autologous stem cell transplant, provided these eligibility criteria are met: transplant was \> 100 days prior to study enrollment, no active infection, subject meets remainder of eligibility criteria outlined in the protocol.

You may not qualify if:

• Chemotherapy, radiotherapy, immunotherapy or other anti-cancer therapy including investigational drugs within 14 days prior to the first dose of any one of the investigational drugs described in this study.
• Current use of prohibited medication during treatment with GSK1120212 and/ or GSK 2110183.
• History of Type 1 diabetes.
• Anticoagulants are permitted only if the subject meets PTT and INR entry criteria. Their use must be monitored in accordance with local institutional practice.
• Presence of active gastrointestinal disease or other condition that could affect gastrointestinal absorption (eg, malabsorption syndrome) or predispose subject to gastrointestinal ulceration.
• Evidence of mucosal or internal bleeding.
• Any major surgery within the last 4 weeks.
• Any serious or unstable pre-existing medical, psychiatric, or other condition (including lab abnormalities) that could interfere with the subject's safety or providing informed consent.
• Known active infection requiring parenteral or oral anti-infective treatment.
• Evidence of severe or uncontrolled systemic diseases (eg, unstable or uncompensated respiratory, hepatic, renal or cardiac disease, unstable hypertension).
• Subjects with brain metastases are excluded if their brain metastases are: symptomatic, treated (surgery, radiation therapy) but not clinically and radiologically stable one month after therapy (as assessed by at least 2 distinct contrast enhanced MRI or CT scans over at least a one month period) OR asymptomatic and untreated but \> 1 cm in the longest dimension.
• Subjects with small (less than or equal to 1cm in the longest dimension), asymptomatic brain metastases that do not need immediate therapy can be enrolled. Subjects with solid tumors on a stable (ie, unchanged) dose of corticosteroids for more than one month, or those who have been off corticosteroids for at least 2 weeks can be enrolled. Subjects must also be off of enzyme-inducing anticonvulsants for more than 4 weeks.
• Subjects with leptomeningeal disease are excluded.
• QTcF interval greater than or equal to 470msecs.
• Subjects with bundle branch block (BBB) or pacemaker.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (2)

GSK Investigational Site

Dallas, Texas, 75246, United States

Location

GSK Investigational Site

San Antonio, Texas, 78229, United States

Location

Related Publications (1)

• Tolcher AW, Patnaik A, Papadopoulos KP, Rasco DW, Becerra CR, Allred AJ, Orford K, Aktan G, Ferron-Brady G, Ibrahim N, Gauvin J, Motwani M, Cornfeld M. Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. Cancer Chemother Pharmacol. 2015 Jan;75(1):183-9. doi: 10.1007/s00280-014-2615-5. Epub 2014 Nov 25.

  PMID: 25417902 DERIVED

Related Links

• Results for study 115829 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Neoplasms; Multiple Myeloma

Interventions

trametinib; GSK2110183

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 13, 2011
• First Posted: November 22, 2011
• Study Start: October 26, 2011
• Primary Completion: March 12, 2013
• Study Completion: March 12, 2013
• Last Updated: November 13, 2017

Record last verified: 2017-11

Locations

US (2)