Ixazomib, Gemcitabine, and Doxorubicin in Treating Patients With Locally Advanced or Metastatic Kidney Cancer

NCT03587662 | Active Not Recruiting Phase 2 FDA Drug

• 2 other identifiers: 2018-0065NCI-2018-01292
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial studies how well ixazomib, gemcitabine, and doxorubicin work in treating patients with kidney cancer that has spread to other places in the body (locally advanced or metastatic). Ixazomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine and doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ixazomib, gemcitabine, and doxorubicin may work better in treating patients with kidney cancer.

Conditions

Metastatic Renal Cell Carcinoma; Metastatic Kidney Medullary Carcinoma; SMARCB1 Negative; Stage III Renal Cell Cancer AJCC v8; Stage IV Renal Cell Cancer AJCC v8

Outcome Measures

Primary Outcomes (2)

• Objective response (complete response or partial response) assessed by Response Evaluation Criteria in Solid (RECIST) 1.1

  Up to 2 years

• Disease control (stable disease or better) measured by RECIST 1.1

  At week 28

Secondary Outcomes (6)

• Incidence of adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0

  Up to 2 years

• Overall survival

  From treatment start date until death from any cause (event) or last contact date for patients last known to be alive (censor), assessed up to 2 years

• Progression-free survival

  From treatment start date until progression (event) or death from any cause (event), assessed up to 2 years

• Duration of response

  From first documented response until progression (event) or death from any cause (event), assessed up to 2 years

• Biomarker analysis of biomarkers PDI, BiP, eIF2aP assessed in tumor tissue samples

  Up to 2 years

Study Arms (1)

Treatment (ixazomib, gemcitabine, doxorubicin)

EXPERIMENTAL

INDUCTION: Patients receive ixazomib PO, gemcitabine IV over 90 minutes, and doxorubicin IV over 15-30 minutes on day 1. Treatment repeats every 14 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive ixazomib PO and gemcitabine IV over 90 minutes. Cycles repeat every 14 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Drug: Doxorubicin; Drug: Doxorubicin Hydrochloride; Drug: Gemcitabine; Drug: Gemcitabine Hydrochloride; Drug: Ixazomib; Drug: Ixazomib Citrate

Interventions

Doxorubicin DRUG

Given IV

Also known as: Adriablastin, Hydroxydaunomycin, Hydroxyl Daunorubicin, Hydroxyldaunorubicin

Treatment (ixazomib, gemcitabine, doxorubicin)

Doxorubicin Hydrochloride DRUG

Given IV

Also known as: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin HCl, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, hydroxydaunorubicin, Rubex

Treatment (ixazomib, gemcitabine, doxorubicin)

Gemcitabine DRUG

Given IV

Also known as: dFdC, dFdCyd, Difluorodeoxycytidine

Treatment (ixazomib, gemcitabine, doxorubicin)

Gemcitabine Hydrochloride DRUG

Given IV

Also known as: dFdCyd, Difluorodeoxycytidine Hydrochloride, FF 10832, FF-10832, FF10832, Gemcitabine HCI, Gemzar, LY-188011, LY188011

Treatment (ixazomib, gemcitabine, doxorubicin)

Ixazomib DRUG

Given PO

Also known as: MLN-2238, MLN2238

Treatment (ixazomib, gemcitabine, doxorubicin)

Ixazomib Citrate DRUG

Given PO

Also known as: MLN-9708, MLN9708, Ninlaro

Treatment (ixazomib, gemcitabine, doxorubicin)

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with locally advanced or metastatic RMC histologically confirmed by expert pathology review and loss of SMARCB1 staining by immunohistochemistry. Also eligible are patients with other rare SMARCB1-negative tumors of the kidney, such as advanced or metastatic unclassified renal cell carcinoma with medullary phenotype (a rare RMC variant occurring in individuals without sickle hemoglobinopathies), and adult-onset malignant rhabdoid tumors. The principal investigator (PI) is the final arbiter in questions related to eligibility.
• Patients will be eligible regardless of whether they have had prior nephrectomy or still have their primary tumor in-situ. Patients with prior nephrectomy can be screened for enrollment at any time following the procedure.
• Patients must have at least one measurable site of disease, defined as a lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) and measures \>= 15 mm with conventional techniques or \>= 10 mm with more sensitive techniques such as magnetic resonance imaging (MRI) or spiral computed tomography (CT) scan. If the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation. Patients with disease confined to bone may be eligible if a measurable lytic defect is present or a serum marker is elevated (\> 4 x upper limit of normal \[ULN\]). The PI is the final arbiter in questions related to measurability.
• Patients can have received prior immunotherapies such as anti-PD1, anti-PD-L1, or anti-CTLA-4 immune checkpoint inhibitors, or targeted therapies such as sunitinib, pazopanib, axitinib, cabozantinib, bevacizumab, erlotinib, and everolimus, or any cytotoxic chemotherapy regimens with the exception of regimens using a combination of gemcitabine \>= 800 mg/m\^2 plus adriamycin \>= 30 mg/m\^2. In addition, the total lifetime dose of doxorubicin prior to enrollment must not exceed 382 mg/m\^2 as these would preclude patients from receiving at least 4 cycles of induction therapy of the trial protocol. Patients must not have received any proteasome inhibitors such as bortezomib or carfilzomib.
• There must be evidence of progression on or after last treatment regimen received.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2. NOTE: If subject is unable to walk due to paralysis, but is mobile in a wheelchair, subject is considered to be ambulatory for the purpose of assessing their performance status.
• Adolescent patients age 12 years and older are allowed with signed assent and parental consent according to institutional guidelines and requirements, as long as their body surface area (BSA) is \>=1.2 given that this is the lower limit for which the independence between BSA and ixazomib exposure has been ascertained.
• Hemoglobin \>= 9 g/dl (treatment allowed). May receive transfusion (within 14 days of the first dose of the study drugs).
• Absolute neutrophil count \>= 1000/uL. Without growth factor support (filgrastim or pegfilgrastim) for at least 14 days (within 14 days of the first dose of the study drugs).
• Platelets \>= 75,000/uL. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment (within 14 days of the first dose of the study drugs).
• Total bilirubin =\< 1.5 mg/dl. For patients with Gilbert's disease, total bilirubin should be =\< 3 mg/dL (=\< 51.3 umol/L) (within 14 days of the first dose of the study drugs).
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\]) or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 X institutional ULN, except in known hepatic metastasis, wherein may be =\< 5 x ULN as per current American Society of Clinical Oncology recommendations. Approximately 15% of patients with RMC develop liver metastases (within 14 days of the first dose of the study drugs).
• Creatinine clearance \> 30 mL/kg/1.73 m\^2. If creatinine is not \< 1.5 x ULN, then calculate by Cockcroft-Gault methods or local institutional standard (within 14 days of the first dose of the study drugs).
• International normalized ratio (INR) and partial thromboplastin time (PTT) =\< 1.5 x ULN prior to study entry. Therapeutic anticoagulation with warfarin is allowed if target INR =\< 3 on a stable dose of warfarin or other oral anticoagulant, or on a stable dose of low molecular weight (LMW) heparin for \> 2 weeks (14 days) at the time of enrollment. Patients who have liver metastases resulting in INR and/or PTT \> 1.5 x ULN and require chronic (\>= 3 months) anticoagulation are not allowed.
• Patients must have a measured ejection fraction of at least 45% as measured by either multigated acquisition (MUGA) scan, echocardiogram, stress test, or ventriculography.

You may not qualify if:

• Patients diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. Patients with another malignancy on watch and wait without any needing of treatment can be enrolled in this study.
• Patients must not have received anticancer therapies (including chemotherapy and targeted therapy) within 2 weeks (14 days) or 5 half-lives (whichever is shorter) prior to study day 1. Patients who have completed palliative radiation therapy more than 14 days prior to study day 1 are eligible. If the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the ixazomib.
• Patients, who have had a major surgery or significant traumatic injury (injury requiring \> 4 weeks \[28 days\] to heal) within 4 weeks (28 days) of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that are expected to require major surgery, other than cytoreductive nephrectomy +/- retroperitoneal lymph node dissection, during the course of the study.
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
• Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBVsAg) test (regardless of HBV deoxyribonucleic acid \[DNA\] levels or IgM hepatitis B virus core antibody \[anti-HBc\] status) or positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV antibody test indicating acute or chronic infection. If hepatitis C antibody test is positive then active infection has to be confirmed by hepatitis C RNA testing for the patient to be excluded.
• Patient has \>= grade 3 peripheral neuropathy, or grade 2 peripheral neuropathy with pain on clinical examination during the screening period.
• Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib, including difficulty swallowing, refractory nausea and vomiting, uncontrolled diarrhea, malabsorption, significant small bowel resection or gastric bypass surgery, use of feeding tubes. The PI is the final arbiter in questions related to eligibility.
• Systemic treatment, within 14 days before the first dose of ixazomib, with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort.
• Patients receiving any concomitant systemic therapy for renal cell cancer are excluded.
• Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial.
• Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
• Symptomatic congestive heart failure of New York heart Association class III or IV.
• Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease.
• Severely impaired lung function as defined as oxygen (O2) saturation that is 92% or less at rest on room air.
• Uncontrolled diabetes as defined by fasting serum glucose \> 1 .5 x ULN.

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Links

• MD Anderson Cancer Center Website

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

Doxorubicin; Gemcitabine; ixazomib; MLN2238

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Study Officials

• Pavlos Msaouel

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: July 2, 2018
• First Posted: July 16, 2018
• Study Start: August 17, 2018
• Primary Completion (Estimated): January 31, 2027
• Study Completion (Estimated): January 31, 2027
• Last Updated: January 9, 2026

Record last verified: 2026-01

Locations

US (1)