Ph 1b Study to Evaluate GSK2110183 in Combination With Bortezomib and Dexamethasone in Subjects With Multiple Myeloma

NCT01428492 | Completed Phase 1

• 1 other identifier: 115125
• Study Type: interventional
• Target: 90
• Locations: 5 countries
• Sites: 13

Brief Summary

Phase Ib, open-label study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of GSK2110183 dosed in combination with bortezomib and dexamethasone in multiple myeloma (MM) subjects who have failed at least one line of systemic treatment. Part 1 will identify the maximum tolerated dose(s) (MTD) of the combination regimen. Schedule A - GSK2110183 administered once daily with bortezomib (1.3 mg/m2) and dexamethasone (20 mg) given biweekly. Part 2 will further explore the safety, tolerability and clinical activity of the MTD(s) identified in Part 1, including a pharmacokinetic cohort.

Conditions

Multiple Myeloma

Keywords

AKT Inhibitor; hematologic malignancies; GSK2110183; bortezomib; multiple myeloma; dexamethasone

Outcome Measures

Primary Outcomes (1)

• The recommended Phase II dose (RP2D) and schedule of GSK2110183, bortezomib and dexamethasone dosed in combination.

  Dose and schedule determined using adverse events and changes in safety assessments (laboratory parameters, vital signs and ECG parameters). Recommended Phase 2 Dose (RP2D) will be defined in Part 1. The specific number of subjects to be enrolled is dependent on the number of dose limiting toxicities (DLTs) reported; enrollment of up to 45 subjects in Part 1 is estimated. Subjects will continue on study from the date of randomization until the date of the first documented disease progression or when the subject meets one of the Treatment Discontinuation criteria, whichever comes first

  Estimation is that each subject may be assessed for up to 48 months.

Secondary Outcomes (4)

• Pharmacokinetics of GSK2110183, bortezomib and dexamethasone. Composite (or Profile) of Pharmacokinetics Time Frame: predose, 0, 5 min, 15 min, 1, 2, 3, 4, 6, 8, 10-12, 14-22, and 24 hrs post-dose.

  Part 2, PK plasma samples will be collected on Cycle 0 Day 11 and Day 38 and Cycle 1 Day 11 (each day at predose, 5min, 15min, 1, 2, 3, 4, 6, 8, 10-12, 14-22 and 24 hrs). Part 1 and Part 2, 3 PK plasma samples will be collected on Day 1 of Cycles 2 - 8

• Clinical activity

  Lab assessment of disease (i.e., quantitative paraprotein, SPEP/UPEP) occurs at beginning of cycles, or every 3 wks. Extramedullary disease assessed every 12 wks by imaging, only as warranted.

• Relationships between GSK2110183, Pharmacokinetic (PK), Pharmacodynamic (PD) and clinical activity. Composite (or Profile) of Serial Pharmacokinetics Time Frame: predose, 5 min, 15 min, 1,2,3,4,6,8, 10-12, 14-22, and 24 hours post-dose.

  Part 2, serial PK plasma samples will be collected on Cycle 0 Day 11 and Day 38 and Cycle 1 Day 11. In Part 1 and 2, PD markers (BM biopsy and aspirite, plasma for cfDNA and CAF) will be collected predose, once post dose and at time of relapse.

• Exploratory Translational Research

  BM biopsy for AKT activation markers (predose, once post dose). Plasma for cfDNA and CAFs (predose, once post dose, at time of relapse). BM aspirate to assess potential predictive markers of response: FISH (predose) and cytogenetics (predose and CR).

Study Arms (3)

Part 1-Dose Escalation

EXPERIMENTAL

GSK2110183 is administered in combination with bortezomib and dexamethasone until MTD is met.

Drug: GSK2110183; Drug: Bortezomib; Drug: Dexamethasone

Part 2- Pharmacokinetic/Pharmacodynamics Cohort

EXPERIMENTAL

Once the MTD(s) has been determined, up to 9 subjects of the total enrolled in Part 2 will be entered in the Pharmacokinetic/Pharmacodynamic Cohort. Subjects will be enrolled in this cohort to explore whether exposure to GSK2110183 at dose identified in Part 1 is similar when GSK2110183 is administered alone or in combination with bortezomib and dexamethasone. The same relationship will be explored for bortezomib and dexamethasone when the two drugs are give alone or in combination with GSK2110183.

Drug: GSK2110183; Drug: Bortezomib; Drug: Dexamethasone

Part 2- Safety/Clinical Activity Cohort

EXPERIMENTAL

Enrolment into the safety/clinical activity cohort in Part 2 will begin prior to enrollment in the PK/PD cohort. Subjects with relapsed multiple myeloma who are either bortezomib sensitive or naive after failing one line of prior systemic therapy will be enrolled in the Safety/Clinical Activity cohort. "Bortezomib sensitive" is defined as having a response (PR or better) to the last bortezomib-containing therapy lasting at least 60 days beyond the end of therapy. A minimum of 15 subjects and a total of 40 subjects will be enrolled. This expansion cohort will further characterize the safety and clinical activity profile of GSK2110183 to inform the future development of this combination regimen.

Drug: GSK2110183; Drug: Bortezomib; Drug: Dexamethasone

Interventions

GSK2110183 DRUG

The oral, once daily dose of GSK2110183 will be dependent on the cohort to which a subject is assigned. Subjects enrolled in Cohort 1 will receive 75 mg GSK2110183 once daily. Dose escalation in Schedule A and Schedule B will follow 25 mg increments in a 3+3 dose escalation procedure up to a maximum of 150mg daily or until MTD is reached, whichever comes first, for each schedule. GSK2110183 will continue at daily dosing until treatment discontinuation criteria is met.

Part 1-Dose Escalation; Part 2- Pharmacokinetic/Pharmacodynamics Cohort; Part 2- Safety/Clinical Activity Cohort

Bortezomib DRUG

Bortezomib (1.0 mg/m2) will be administered on days 1, 4, 8, and 11 of each 21-day cycle for cohort 1 for up to 8 cycles. Bortezomib (1.3 mg/m2) will be administered on days 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles. Bortezomib (1.5 mg/m2) will be administered on days 1, 8, and 15 of each 21-day cycle for up to 8 cycles.

Part 1-Dose Escalation; Part 2- Pharmacokinetic/Pharmacodynamics Cohort; Part 2- Safety/Clinical Activity Cohort

Dexamethasone DRUG

Dexamethasone will be given orally at a fixed dose of 20 mg only on days of bortezomib dosing in both Schedule A and Schedule B.

Part 1-Dose Escalation; Part 2- Pharmacokinetic/Pharmacodynamics Cohort; Part 2- Safety/Clinical Activity Cohort

Eligibility Criteria

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

You may qualify if:

• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• Male or female, 18 years or older.
• Performance status score of 0 - 2 according to the Eastern Cooperative Oncology Group (ECOG) scale.
• Able to swallow and retain oral medication.
• Histologically confirmed diagnosis of Multiple Myeloma (MM). Subjects enrolled in the Safety/Clinical Activity Cohort (Part 2) must have relapsed MM (bortezomib-naive or bortezomib sensitive) with at least one of the following: Serum M-protein ≥1.0g/dl (≥10gm/l); Urine M-protein ≥200 mg/24h; Serum Free Light Chain (FLC) assay: Involved FLC level ≥5mg/dl (≥50mg/l) and an abnormal serum free light chain ratio (\<0.26 or \>1.65); Biopsy proven plasmacytoma (should be measured within 28 days of Screening Visit)
• Failed at least 1 line of systemic therapy. The preparative regimen (with or without total body irradiation) and subsequent autologous stem cell rescue used for an autologous stem cell transplant are considered as one line of therapy.
• Subjects with a history of autologous stem cell transplant are eligible for study participation provided the following eligibility criteria are met:
• transplant was \> 100 days prior to study enrolment
• no active infection
• subject meets the remainder of the eligibility criteria outlined in this protocol
• Fasting serum glucose \<126 mg/dL (\<7 mmol/L). Subjects diagnosed previously with Type 2 diabetes must also meet the additional following criteria:
• Diagnosis of diabetes ≥6 months prior to enrolment
• HbA1c≤8% at Screening visit
• Adequate organ system function as defined in protocol.
• A female subject is eligible to participate if she is of non-childbearing potential (i.e. physiologically incapable of becoming pregnant) defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 MIU/ml and estradiol \<40 MIU/ml and estradiol \<40 pg/ml (\<147pmol/L) is confirmatory. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in the protocol if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.

You may not qualify if:

• Chemotherapy, radiotherapy, immunotherapy, or other anti-myeloma therapy within 14 days prior to the first dose of any one of the drugs in the combination regimen. In addition, any drug-related toxicity should have recovered to Grade 1 or less.
• Use of an investigational drug within 14 days or five half-lives, whichever is shorter, preceding the first dose of any one of the drugs in the combination regimen.
• Current use of prohibited medication listed in the protocol during treatment with GSK2110183.
• Current use of oral corticosteroids, with the exception of inhaled or topical steroids. Dexamethasone will be given only in combination with bortezomib on this study.
• Anticoagulants are permitted only if the subject meets Partial Thromboplastin Time (PTT) and International Normalized Ratio (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 (e.g. malabsorption syndrome) or predispose subject to gastrointestinal ulceration.
• Evidence of mucosal or internal bleeding.
• Presence of \> Grade 1 peripheral neuropathy at screening.
• Unresolved toxicity (except alopecia) ≥ Grade 2 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 \[NCI-CTCAE, 2009\] from previous anti-cancer therapy.
• Any major surgery within the last four weeks.
• Type 1 diabetes mellitus.
• Any serious or unstable pre-existing medical, psychiatric, or other condition (including lab abnormalities) that could interfere with subject's safety or providing informed consent.
• Known active infection requiring parenteral or oral anti-infective treatment.
• Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal or cardiac disease, unstable hypertension).
• Primary or metastatic malignancy of the central nervous system.

Sponsors & Collaborators

• Novartis: lead

Study Sites (13)

Novartis Investigative Site

Scottsdale, Arizona, 85259, United States

Location

Novartis Investigative Site

Duarte, California, 91010, United States

Location

Novartis Investigative Site

Atlanta, Georgia, 30322, United States

Location

Novartis Investigative Site

Chicago, Illinois, 60637, United States

Location

Novartis Investigative Site

New York, New York, 10029, United States

Location

Novartis Investigative Site

Chapel Hill, North Carolina, 27599-7305, United States

Location

Novartis Investigative Site

Columbus, Ohio, 43210, United States

Location

Novartis Investigative Site

Madison, Wisconsin, 53792, United States

Location

Novartis Investigative Site

Melbourne, Victoria, 3004, Australia

Location

Novartis Investigative Site

Vancouver, British Columbia, V5Z 1M9, Canada

Location

Novartis Investigative Site

Toronto, Ontario, M5G 2M9, Canada

Location

Novartis Investigative Site

Galway, Ireland

Location

Novartis Investigative Site

Taipei, 100, Taiwan

Location

MeSH Terms

Conditions

Multiple Myeloma; Hematologic Neoplasms

Interventions

GSK2110183; Bortezomib; Dexamethasone

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; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

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

Study Record Dates

• First Submitted: August 11, 2011
• First Posted: September 5, 2011
• Study Start: December 1, 2011
• Primary Completion: October 1, 2015
• Study Completion: October 1, 2015
• Last Updated: August 8, 2018

Record last verified: 2018-08

Locations

IE (1); TW (1); CA (2); AU (1); US (8)