Dinaciclib, Bortezomib, and Dexamethasone in Treating Patients With Relapsed Multiple Myeloma

Phase 1 Clinical Trial of a Novel CDK Inhibitor Dinaciclib (SCH 727965) in Combination With Bortezomib and Dexamethasone in Relapsed Multiple Myeloma

This phase I trial studies the side effects and best dose of dinaciclib and bortezomib when given together with dexamethasone in treating patients with multiple myeloma that has returned after a period of improvement. Dinaciclib and bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving dinaciclib and bortezomib together with dexamethasone may kill more cancer cells.

Study Overview

• Status: Completed
• Conditions: Recurrent Plasma Cell Myeloma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Dinaciclib; Drug: Dexamethasone; Drug: Bortezomib

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximally tolerated doses of dinaciclib and bortezomib, when used in combination, in two different schedules, for treatment of relapsed multiple myeloma.

SECONDARY OBJECTIVES:

I. To determine the toxicities associated with dinaciclib and bortezomib, when used in combination, for treatment of relapsed multiple myeloma.

II. To determine the overall response rate associated with dinaciclib and bortezomib, when used in combination, for treatment of relapsed multiple myeloma.

III. To explore the differences in toxicity associated with two different schedules of dinaciclib and bortezomib used in combination.

TERTIARY OBJECTIVES:

I. To examine if expression levels of target cyclin dependent kinase (CDK): CDK 2,5,7 and 9 levels in cluster of differentiation (CD)138-purified tumor cells, will be correlated with response (clinical and molecular) to determine if high or low level target CDK expression, if present, influences dinaciclib efficacy.

II. To examine if immunoglobulin (Ig)H translocation status, P53 status and presence of v-myc myelocytomatosis viral oncogene homolog (avian) (Myc) amplification or rearrangement, determined on patient bone marrow before treatment, using a pre validated fluorescence in situ hybridization (FISH) panel to identify common myeloma translocations, will be correlated with molecular and/or clinical markers of drug activity, and to assess if specific genetic subgroups of myeloma tumors are responsive or resistant.

III. To determine the gene expression profiles of myeloma cells before and after treatment to understand the role of tumor gene dysregulation and/or dinaciclib induced effects on transcription.

OUTLINE: This is a dose-escalation study of dinaciclib and bortezomib. Patients are assigned to 1 of 2 treatment schedules.

SCHEDULE I: Patients receive dinaciclib intravenously (IV) over 2 hours and bortezomib subcutaneously (SC) or IV (if patients do not tolerate SC injection) on days 1, 8, and 15 and dexamethasone orally (PO) once daily (QD) on days 1, 2, 8, 9, 15, and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

SCHEDULE II: Patients receive dinaciclib IV over 2 hours on day 1; bortezomib SC on days 1 and 8; and dexamethasone PO QD on days 1, 2, 8, and 9. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and 3 months.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic in Arizona
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University/Massey Cancer Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics
    • Wisconsin Rapids, Wisconsin, United States, 54494
      • Aspirus UW Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Serum creatinine =< 2.5 mg/dL
• Absolute neutrophil count >= 1000/uL
• Untransfused platelet count >= 75000/uL
• Hemoglobin >= 8 g/dL
• Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)
• Patients with relapsed multiple myeloma who have already received one or more standard treatment regimens

• Measurable disease of multiple myeloma as defined by at least ONE of the following:

  • Serum monoclonal protein >= 1 g/dL
  • >= 200 mg of monoclonal protein in the urine on 24 hour electrophoresis
  • Serum immunoglobulin free light chain >= 10 mg/dL and abnormal serum immunoglobulin kappa to lambda free light chain ratio
  • Monoclonal bone marrow plasmacytosis >= 30% (evaluable disease)
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
• Adequate residual organ function per treating physician discretion; Note: there is no limit with regard to the number of prior therapies
• Provide informed written consent
• Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
• Willing to provide samples for correlative research purposes
• Willing to return to consenting institution for follow-up during the study
• Recovered (i.e., =< grade 1 toxicity) from the reversible effects of prior antineoplastic therapy

Exclusion Criteria:

• Any of the following recent therapies:

  • Alkylators (e.g. melphalan, cyclophosphamide) =< 14 days prior to registration
  • Anthracyclines =< 14 days prior to registration
  • High dose corticosteroids, immune modulatory drugs (thalidomide or lenalidomide), or proteosome inhibitors (bortezomib) =< 7 days prior to registration
• Concomitant high dose corticosteroids (concurrent use of corticosteroids); EXCEPTION: patients may be on chronic steroids (maximum dose 20 mg/day prednisone equivalent) if they are being given for disorders other than amyloid, i.e., adrenal insufficiency, rheumatoid arthritis, etc.
• Other active malignancy =< 2 years prior to registration; EXCEPTIONS: non-melanotic skin cancer or carcinoma in-situ of the cervix; NOTE: if there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer

• Any of the following:

  • Pregnant women or women of reproductive ability who are unwilling to use 2 effective methods of contraception from the time of signing the informed consent form through 30 days after the last dose of study drug
  • Nursing women
  • Men who are unwilling to use a condom (even if they have undergone a prior vasectomy) while having intercourse with any woman, while taking the drug and for 30 days after stopping treatment
• Other co-morbidity which would interfere with patient's ability to participate in trial, e.g. uncontrolled infection, uncompensated heart or lung disease
• Other concurrent chemotherapy, radiotherapy, or any ancillary therapy considered investigational; NOTE: bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment
• Peripheral neuropathy >= grade 2 on clinical examination during the screening period
• Major surgery =< 14 days prior to registration
• Currently taking strong or moderate inhibitors/inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4); Note: dinaciclib is a CYP3A4 substrate; patients should not take grapefruit/grapefruit juice or St. John's wort; use of strong or moderate CYP3A4 inhibitors is prohibited from < 7 days prior to registration; use of CYP3A4 inducers is prohibited from =< 7 days prior to registration

• Any of the following conditions:

  • Myocardial infarction =< 6 months prior to registration or has New York Heart Association (NYHA) class III or IV heart failure
  • Uncontrolled angina
  • Severe uncontrolled ventricular arrhythmias
  • Electrocardiographic evidence of acute ischemia
  • Active conduction system abnormalities; NOTE: prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevant
• Known hypersensitivity to bortezomib, boron, or mannitol
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study per the judgment of the treating physician

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Schedule I (dinaciclib, bortezomib, dexamethasone); Patients receive dinaciclib IV over 2 hours and bortezomib SC or IV (if patients do not tolerate SC injection) on days 1, 8, and 15 and dexamethasone PO QD on days 1, 2, 8, 9, 15, and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Dinaciclib; Given IV; Other Names: SCH 727965; MK-7965; CDK Inhibitor SCH 727965; Drug: Dexamethasone; Given PO; Other Names: Decadron; Aacidexam; Adexone; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Amplidermis; Anemul mono; Auricularum; Auxiloson; Baycuten; Baycuten N; Cortidexason; Cortisumman; Decacort; Decadrol; Decalix; Decameth; Decasone R.p.; Dectancyl; Dekacort; Deltafluorene; Deronil; Desamethasone; Desameton; Dexa-Mamallet; Dexa-Rhinosan; Dexa-Scheroson; Dexa-sine; Dexacortal; Dexacortin; Dexafarma; Dexafluorene; Dexalocal; Dexamecortin; Dexameth; Dexamethasonum; Dexamonozon; Dexapos; Dexinoral; Dexone; Dinormon; Fluorodelta; Fortecortin; Gammacorten; Hexadecadrol; Hexadrol; Lokalison-F; Loverine; Methylfluorprednisolone; Millicorten; Mymethasone; Orgadrone; Spersadex; Visumetazone; Drug: Bortezomib; Given SC; Other Names: Velcade; MLN341; PS-341; LDP 341; [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid; PS341
Experimental: Schedule II (dinaciclib, bortezomib, dexamethasone); Patients receive dinaciclib IV over 2 hours on day 1; bortezomib SC on days 1 and 8; and dexamethasone PO QD on days 1, 2, 8, and 9. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Dinaciclib; Given IV; Other Names: SCH 727965; MK-7965; CDK Inhibitor SCH 727965; Drug: Dexamethasone; Given PO; Other Names: Decadron; Aacidexam; Adexone; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Amplidermis; Anemul mono; Auricularum; Auxiloson; Baycuten; Baycuten N; Cortidexason; Cortisumman; Decacort; Decadrol; Decalix; Decameth; Decasone R.p.; Dectancyl; Dekacort; Deltafluorene; Deronil; Desamethasone; Desameton; Dexa-Mamallet; Dexa-Rhinosan; Dexa-Scheroson; Dexa-sine; Dexacortal; Dexacortin; Dexafarma; Dexafluorene; Dexalocal; Dexamecortin; Dexameth; Dexamethasonum; Dexamonozon; Dexapos; Dexinoral; Dexone; Dinormon; Fluorodelta; Fortecortin; Gammacorten; Hexadecadrol; Hexadrol; Lokalison-F; Loverine; Methylfluorprednisolone; Millicorten; Mymethasone; Orgadrone; Spersadex; Visumetazone; Drug: Bortezomib; Given SC; Other Names: Velcade; MLN341; PS-341; LDP 341; [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid; PS341

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MTD of dinaciclib and bortezomib when given together with dexamethasone, based on the incidence of dose-limiting toxicity (DLT), graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0	MTD is defined as the dose level below the lowest dose that induces DLT in at least one-third of patients.	Up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events, graded according to NCT CTCAE version 4.0	The number and severity of all adverse events (overall, by dose-level, and by tumor group) will be tabulated and summarized in this patient population. Toxicity is defined as adverse events that are classified as possibly, probably, or definitely related to study treatment. Overall toxicity incidence as well as toxicity profiles by dose level, patient and tumor site will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.	Up to 3 months
Overall response rate	Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population (overall and by tumor group).	Up to 3 months
Time to progression	Summarized descriptively.	Up to 3 months
Time to treatment failure	Summarized descriptively.	From registration to documentation of progression, unacceptable toxicity, or refusal to continue participation by the patients, assessed up to 3 months
Time until hematologic nadirs (absolute neutrophil count, platelets, hemoglobin)	Summarized descriptively.	Up to 3 months

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start (Actual): December 19, 2012
• Primary Completion (Actual): November 22, 2016
• Study Completion (Actual): November 22, 2016

Study Registration Dates

• First Submitted: October 18, 2012
• First Submitted That Met QC Criteria: October 18, 2012
• First Posted (Estimate): October 22, 2012

Study Record Updates

• Last Update Posted (Actual): May 11, 2018
• Last Update Submitted That Met QC Criteria: May 10, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Dermatologic Agents; Dexamethasone; Dexamethasone acetate; BB 1101; Bortezomib; Ichthammol
• Other Study ID Numbers: NCI-2012-01737 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA015083 (U.S. NIH Grant/Contract); UM1CA186716 (U.S. NIH Grant/Contract); U01CA069912 (U.S. NIH Grant/Contract); UM1CA186686 (U.S. NIH Grant/Contract); MC1113 (Other Identifier: Mayo Clinic); NCI 9157; CDR0000741989; 9157 (Other Identifier: CTEP); R01CA167511 (U.S. NIH Grant/Contract)