Trametinib and Akt Inhibitor GSK2141795 in Treating Patients With Relapsed or Refractory Multiple Myeloma

NCT01989598 | Completed Phase 2 Results FDA Drug

• 5 other identifiers: NCI-2013-02148PHL-0919460N01CM00032UM1CA186644
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 5

Brief Summary

This phase II trial studies how well trametinib and Akt inhibitor GSK2141795 work in treating patients with multiple myeloma that has come back (relapsed) or that does not respond to treatment (refractory). Trametinib and Akt inhibitor GSK2141795 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Conditions

Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma

Outcome Measures

Primary Outcomes (1)

• ORR Evidenced by Confirmed Response Rate, Defined as Number of Patients With Partial Response or Better by International Myeloma Working Group (IMWG) Criteria Divided by the Number of Patients in the Applicable Group (Biomarker Positive or Negative)

  "Per International Myeloma Working Group (IMWG) Criteria: Complete Response (CR), Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow; Partial Response (PR), \> 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by \>90% or to \< 200 mg/24 h; Overall Response (OR) = CR + PR."

  Every 4 weeks until progression or death, whichever occurs first, an average of 9 months.

Secondary Outcomes (4)

• PFS

  Time from the date of start of treatment to the date of documented progression (based on IMWG criteria) or death, whichever occurs first, due to any cause, assessed every 4 weeks, an average of 9 months.

• DOR (Duration of Response)

  From time measurement criteria are met for CR or PR (complete or partial response), (whichever recorded first) until first date that recurrent or progressive disease is objectively documented or to death due to multiple myeloma, assessed every 4 weeks

• ORR After the Addition of AKT Inhibitor GSK2141795 to Trametinib in Patients Who Have Developed Progressive Disease or Have Achieved Less Than a PR

  Every 4 weeks until progression or death, whichever occurs first, an average of 9 months.

• Incidence of Adverse Event Reactions Reported According to CTCAE v4.0

  From time of treatment start until treatment completion, an average of 1 year

Other Outcomes (5)

• Pharmacodynamic Markers of Trametinib

  Baseline, day 1 of course 2, progression

• Chromosomal Abnormalities as Determined by FISH

  At baseline

• Tumor Mutational Profile by Next Generation Sequencing

  At baseline

Study Arms (1)

Treatment (trametinib, Akt inhibitor GSK2141795)

EXPERIMENTAL

Patients receive trametinib orally PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease or who achieve less than PR after 4 courses may also receive Akt inhibitor GSK2141795 PO daily on days 1-28.

Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Trametinib; Drug: Uprosertib

Interventions

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (trametinib, Akt inhibitor GSK2141795)

Pharmacological Study OTHER

Correlative studies

Treatment (trametinib, Akt inhibitor GSK2141795)

Trametinib DRUG

Given PO

Also known as: GSK1120212, JTP-74057, MEK Inhibitor GSK1120212, Mekinist

Treatment (trametinib, Akt inhibitor GSK2141795)

Uprosertib DRUG

Given PO

Also known as: GSK2141795, Oral Akt Inhibitor GSK2141795

Treatment (trametinib, Akt inhibitor GSK2141795)

Eligibility Criteria

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

You may qualify if:

• Patients must have histologically or cytologically confirmed multiple myeloma not otherwise specified (NOS) (10028566)
• Patients must have measurable disease as defined as at least one of the following (these baseline laboratory studies for determining eligibility must be obtained within 28 days prior to enrollment):
• Serum M-protein \>= 0.5 g/dl (\>= 5 g/l)
• Urine M-protein \>= 200 mg/24 h
• Serum free light chains (FLC) assay: involved FLC level \>= 10 mg/dl (\>= 100 mg/l) and an abnormal serum free light chain ratio (\< 0.26 or \> 1.65)
• Biopsy proven plasmacytoma (should be measured within 28 days of first study drug administration); prior biopsy is acceptable
• If the serum protein electrophoresis is unreliable for routine M-protein measurement, quantitative immunoglobulin levels on nephelometry or turbidimetry will be followed
• A diagnosis of multiple myeloma (MM) and documentation of relapsed or relapse/refractory status following at least 2 prior lines of therapy
• Documented laboratory (lab) results confirming tumor mutational status must be obtained at screening; patients in whom mutational status cannot be determined will be deemed ineligible
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
• Life expectancy of greater than 6 months
• Able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
• All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version (v)4 grade =\< 1 (except alopecia) at the time of registration; subjects with toxicities attributed to prior anti-cancer therapy which are not expected to resolve and result in long lasting sequelae are permitted to enroll
• Absolute neutrophil count (ANC) \>= 1.0 x 10\^9/L
• Hemoglobin \>= 8 g/dL

You may not qualify if:

• History of another malignancy; exception: patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent second malignancies, are eligible; consult the Cancer Therapy Evaluation Program (CTEP) medical monitor if unsure whether second malignancies meet the requirements specified above
• History of interstitial lung disease or pneumonitis
• Diabetes mellitus currently requiring insulin; subjects with a history of steroid-induced hyperglycemia may be enrolled provided that HbA1C at screening visit is =\< 8%
• Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 28 days prior to randomization and/or daily or weekly chemotherapy or other approved anti-myeloma therapy without the potential for delayed toxicity within 14 days prior to registration
• Use of other investigational drugs within 28 days preceding the first dose of trametinib and during the study
• Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression
• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib or excipients or to dimethyl sulfoxide (DMSO) or GSK214795
• Current use of a prohibited medication; the following medications or non-drug therapies are prohibited:
• Other anti-cancer therapy while on study treatment; (note: megestrol \[Megace\] if used as an appetite stimulant is allowed)
• Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis
• The concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra \[ma huang\], gingko biloba, dehydroepiandrosterone \[DHEA\], yohimbe, saw palmetto, or ginseng)
• In vitro data indicate that GSK2141795 is a cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) substrate; drugs that potently inhibit CYP3A4 could lead to increased GSK2141795 exposure in subjects, and should either be prohibited or used with caution; drugs which are strong inducers of cytochrome P450, family 3, subfamily A (CYP3A) and may result in lower exposures of GSK2141795 should also be prohibited; GSK2141795 also appears to be a moderate in vitro inhibitor of cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) (50% inhibitory concentration \[IC50\] 3 mcM) and CYP3A4 (IC50 11 mcM); drugs that are substrates of CYP3A4 or CYP2C8 with a narrow therapeutic index may be prohibited; drugs that are sensitive substrates of CYP3A4 or CYP2C8 should be used with caution
• History or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED):
• History of RVO or RPED, or predisposing factors to RVO or RPED (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes)
• Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or RPED such as evidence of new optic disc cupping, evidence of new visual field defects, and intraocular pressure \> 21 mmHg

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (5)

Foothills Hospital

Calgary, Alberta, T2N 2T9, Canada

Location

Tom Baker Cancer Centre

Calgary, Alberta, T2N 4N2, Canada

Location

Cross Cancer Institute

Edmonton, Alberta, T6G 1Z2, Canada

Location

Kingston Health Sciences Centre

Kingston, Ontario, K7L 2V7, Canada

Location

University Health Network-Princess Margaret Hospital

Toronto, Ontario, M5G 2M9, Canada

Location

MeSH Terms

Conditions

Multiple Myeloma

Interventions

trametinib; GSK2141795

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; 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

Results Point of Contact

• Title: Dr. Suzanna Trudel
• Organization: Princess Margaret Cancer Centre

Suzanne.Trudel@uhn.ca

4169464501

Study Officials

• Suzanne Trudel

  University Health Network-Princess Margaret Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 18, 2013
• First Posted: November 21, 2013
• Study Start: October 30, 2013
• Primary Completion: August 31, 2019
• Study Completion: September 28, 2020
• Last Updated: March 2, 2022
• Results First Posted: March 2, 2022

Record last verified: 2022-02

Locations

CA (5)