Ixazomib and Dexamethasone With or Without Venetoclax in Treating Patients With Non-t(11;14) Relapsed or Refractory Multiple Myeloma

NCT03856112 | Withdrawn Phase 1 FDA Drug

• 3 other identifiers: NCI-2019-0099410248UM1CA186644
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This phase I/II trial studies the best dose and side effects of venetoclax and how well it works in combination with ixazomib and dexamethasone in treating patients with t(11;14) negative multiple myeloma that has come back or does not respond to treatment. Ixazomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as venetoclax and 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. It is not yet known how well venetoclax works with ixazomib and dexamethasone in treating patients with multiple myeloma.

Conditions

Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma; t(11;14) Negative

Outcome Measures

Primary Outcomes (3)

• Maximum tolerated dose/recommended phase II dose (MTD/RP2D) of venetoclax (Phase I)

  The MTD is defined as the highest dose level in which 1 or fewer of 6 patients experience a dose limiting toxicity. That dose level is considered the MTD/RP2D.

  Up to 28 days

• Overall response rate (ORR) (Phase II)

  For cohort 1, the difference in ORR between the two arms will be tested by using the Cochran-Mantel-Haenszel (CMH) test.

  Up to 2.5 years

• Overall response rate (ORR) (Phase II)

  For cohort 2, the ORR will be estimated, and the lower limit of the one-sided 90% confidence interval (CI) will be computed using the Atkinson and Brown method (Atkinson and Brown 1985), which accounts for the nature of a two-stage design.

  Up to 2.5 years

Secondary Outcomes (13)

• Very good partial response (VGPR) or better response rate

  Up to 2.5 years

• Time to progression (TTP)

  From the date of the first dose of study drug (cohort 2) or date of randomization (cohort 1) to the date of first documented progressive disease (PD) or death due to multiple myeloma, whichever occurs first, assessed up to 2.5 years

• Time to progression (TTP)

  From the date of the first dose of study drug (cohort 2) or date of randomization (cohort 1) to the date of first documented PD or death due to multiple myeloma, whichever occurs first, assessed up to 2.5 years

• Time to progression (TTP)

  From the date of the first dose of study drug (cohort 2) or date of randomization (cohort 1) to the date of first documented PD or death due to multiple myeloma, whichever occurs first, assessed up to 2.5 years

• Progression-free survival (PFS)

  From the date of the first dose of study drug (cohort 2) or date of randomization (cohort 1) to the date of first documented PD or death due to any cause, whichever occurs first, assessed up to 2.5 years

Other Outcomes (6)

• BCL2 biomarker analysis

  At screening and day 8

• BCL2 biomarker analysis

  At screening and day 8

• NOXA biomarker analysis

  At screening and day 8

Study Arms (3)

Arm I (ixazomib, venetoclax, dexamethasone)

EXPERIMENTAL

Patients receive ixazomib citrate PO on days 1, 8, and 15, venetoclax PO QD on days 1-28 and dexamethasone PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Dexamethasone; Drug: Ixazomib; Drug: Ixazomib Citrate; Drug: Venetoclax

Arm II (ixazomib, dexamethasone)

ACTIVE COMPARATOR

Patients receive ixazomib citrate PO on days 1, 8, and 15, and dexamethasone PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Dexamethasone; Drug: Ixazomib; Drug: Ixazomib Citrate

Arm III (ixazomib, venetoclax, dexamethasone)

EXPERIMENTAL

PI-refractory patients receive ixazomib citrate, venetoclax and dexamethasone as Arm I.

Drug: Dexamethasone; Drug: Ixazomib; Drug: Ixazomib Citrate; Drug: Venetoclax

Interventions

Dexamethasone DRUG

Given PO

Also known as: Aacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, 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

Arm I (ixazomib, venetoclax, dexamethasone); Arm II (ixazomib, dexamethasone); Arm III (ixazomib, venetoclax, dexamethasone)

Ixazomib DRUG

Given PO

Also known as: MLN-2238, MLN2238

Arm I (ixazomib, venetoclax, dexamethasone); Arm II (ixazomib, dexamethasone); Arm III (ixazomib, venetoclax, dexamethasone)

Ixazomib Citrate DRUG

Given PO

Also known as: MLN-9708, MLN9708, Ninlaro

Arm I (ixazomib, venetoclax, dexamethasone); Arm II (ixazomib, dexamethasone); Arm III (ixazomib, venetoclax, dexamethasone)

Venetoclax DRUG

Given PO

Also known as: ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta

Arm I (ixazomib, venetoclax, dexamethasone); Arm III (ixazomib, venetoclax, dexamethasone)

Eligibility Criteria

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

You may qualify if:

• ELIGIBILITY CRITERIA FOR PHASE I AND PHASE II
• Patients must have RRMM without t(11;14), confirmed by fluorescence in situ hybridization (FISH).
• RRMM with measurable disease with at least one of the following: M-protein \>= 0.5 g/dL in serum or \>= 200 mg/24-hour in urine, or serum free light chain (FLC) \>= 10 mg/dL with abnormal serum FLC ratio for subjects without measurable disease by serum protein electrophoresis (SPEP) or urine protein electrophoresis (UPEP) criteria.
• Prior multiple myeloma (MM) treatment:
• Received at least 2 lines of prior therapy (including at least one PI, excluding MLN9708), or
• Received 1 prior line of therapy with both a PI (excluding MLN9708) and an immunomodulatory (IMiD) agent.
• PI-refractory (only applicable to phase 2, cohort 2): progressing =\< 60 days of the last PI therapy or \< 25% response while on therapy.
• PI-non-refractory (only applicable to phase 2, cohort 1): not meeting PI-refractory criteria, i.e., (a) did not progress =\< 60 days of the last PI therapy and (b) had \>= 25% response while on therapy.
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%).
• Absolute neutrophil count (ANC) \>= 1,000/mcL (patients may not use growth factor support to achieve ANC criteria for eligibility assessment).
• Platelets \>= 50,000/mcL (patients may not receive a platelet transfusion within 72 hours of eligibility assessment).
• Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN).
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase \[SGPT\]) =\< 3.0 x institutional ULN.
• Calculated creatinine clearance \>= 30 mL/min (measured by either 24-hour urine collection or calculated using the Cockcroft-Gault formula).
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

You may not qualify if:

• Patients who have been previously treated with MLN9708 or venetoclax or other direct BCL2 inhibitor.
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities grade \> 1), except for grade 2 peripheral sensory neuropathy.
• Patients who are receiving any other anti-myeloma chemotherapy or radiotherapy, immunotherapy, or investigational agents within 2 weeks or 5 half-lives (whichever is longer and/or applicable) of the start of the trial.
• Patients receiving dexamethasone \>= 40 mg/day or equivalent of any corticosteroids within 2 weeks of the start of the trial.
• Patients with non-secretory MM, plasma cell leukemia (i.e., \>= 20% plasma cells in peripheral blood differential or \>= 2,000/mcL circulating plasma cells), symptomatic primary light chain (AL) amyloidosis, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
• Prior allogeneic hematopoietic cell transplantation (HCT) within the last 12 months and evidence of active graft-versus-host disease (GVHD).
• Prior autologous HCT within the last 3 months.
• History of active malignancies other than MM within the last 2 years unless treated with curative intent and has no evidence of active disease. Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin are excluded from this criterion.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to MLN9708, venetoclax, or dexamethasone. This includes boron and boron-containing products.
• Patients requiring chronic administration of any medications or substances that are strong inhibitors or inducers of CYP3A4 enzyme are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
• Patients with uncontrolled intercurrent illness.
• Female patients who are lactating or have a positive serum pregnancy test during the screening period are excluded from this study because MLN9708 is a proteasome inhibitor with the potential for embryo-lethal effects, and an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with MLN9708. Patients must stop breastfeeding while on MLN9708 and until 90 days have passed since their last dose. These potential risks may also apply to other agents used in this study.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Dexamethasone; Calcium Dobesilate; auricularum; dexamethasone acetate; dexamethasone 21-phosphate; ixazomib; MLN2238; venetoclax

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

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Study Officials

• Taiga Nishihori

  University Health Network Princess Margaret Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: February 22, 2019
• First Posted: February 27, 2019
• Study Start: June 21, 2019
• Primary Completion: December 31, 2021
• Study Completion: December 31, 2021
• Last Updated: March 26, 2019

Record last verified: 2019-03