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Trial of Ixazomib Combined With Gemcitabine and Doxorubicin in Patients With Renal Medullary Carcinoma

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ClinicalTrials.gov Identifier: NCT03587662
Recruitment Status : Recruiting
First Posted : July 16, 2018
Last Update Posted : August 27, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

Any time the words "you," "your," "I," or "me" appear, it is meant to apply to the potential participant.

The goal of this clinical research study is to learn if the combination of ixazomib, gemcitabine, and doxorubicin can help to control renal medullary carcinoma (RMC).

This is an investigational study. Ixazomib is FDA approved and commercially available for the treatment of multiple myeloma. Gemcitabine and doxorubicin are FDA approved and commercially available for several other types of cancer such as urothelial or bladder cancer. It is considered investigational to use ixazomib, gemcitabine, and doxorubicin to treat RMC.

The study doctor can explain how the study drugs are designed to work.

Up to 30 participants will be enrolled in this study. All will take part at MD Anderson


Condition or disease Intervention/treatment Phase
Kidney Medullary Carcinoma Stage III Renal Cell Cancer AJCC v8 Stage IV Renal Cell Cancer AJCC v8 Drug: Doxorubicin Drug: Gemcitabine Drug: Ixazomib Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of Ixazomib Combined With Gemcitabine and Doxorubicin in Patients With Renal Medullary Carcinoma
Actual Study Start Date : August 17, 2018
Estimated Primary Completion Date : January 6, 2021
Estimated Study Completion Date : January 6, 2021


Arm Intervention/treatment
Experimental: Treatment (ixazomib, gemcitabine, doxorubicin)

INDUCTION: Participants 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 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Participants receive ixazomib PO and gemcitabine IV over 90 minutes. Courses repeat every 14 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Drug: Doxorubicin
Given IV
Other Names:
  • Adriablastin
  • Hydroxyl Daunorubicin
  • Hydroxydaunorubicin

Drug: Gemcitabine
Given IV
Other Names:
  • dFdC
  • dFdCyd
  • Difluorodeoxycytidine

Drug: Ixazomib
Given PO
Other Names:
  • MLN-2238
  • MLN2238




Primary Outcome Measures :
  1. Objective response (complete response or partial response) assessed by Response Evaluation Criteria in Solid (RECIST) 1.1 [ Time Frame: Up to 2 years ]
  2. Disease control (stable disease or better) measured by RECIST 1.1 [ Time Frame: At week 28 ]

Secondary Outcome Measures :
  1. Incidence of adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 [ Time Frame: Up to 2 years ]
  2. Overall survival [ Time Frame: 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 ]
  3. Progression-free survival [ Time Frame: From treatment start date until progression (event) or death from any cause (event), assessed up to 2 years ]
  4. Duration of response [ Time Frame: From first documented response until progression (event) or death from any cause (event), assessed up to 2 years ]
  5. Biomarker analysis of biomarkers PDI, BiP, eIF2aP assessed in tumor tissue samples [ Time Frame: Up to 2 years ]
  6. IL-6 measured serum samples [ Time Frame: Up to 2 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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.
  2. 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.
  3. 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 MRI or spiral 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 ULN). The PI is the final arbiter in questions related to measurability.
  4. 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/m² plus adriamycin >/= 30 mg/m². In addition, the total lifetime doe of doxorubicin prior to enrollment must not exceed 382 mg/m² 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.
  5. There must be evidence of progression on or after last treatment regimen received.
  6. 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.
  7. Age (at the time of consent/assent): >/=12 years. 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 BSA is >/=1.2 given that this is the lower limit for which the independence between BSA and ixazomib exposure has been ascertained.
  8. Within 14 days of the first dose of the study drugs, patients must have adequate organ and marrow function prior to study entry as defined below: Hemoglobin ^a >/=9 g/dl (treatment allowed); Absolute neutrophil count^b >/= 1000/µL; 3) Platelets ^c >/=75,000/µL; Total Bilirubin ^d </=1.5 mg/dl; AST(SGOT) or ALT (SGPT) </=2.5 X institutional ULN, except in known hepatic metastasis, wherein may be </=5 x ULN^e as per current American Society of Clinical Oncology recommendations^45- Creatinine clearance^f >30 mL/kg/1.73 m^2
  9. CONTINUE FROM 8: ^aMay receive transfusion; ^b Without growth factor support (filgrastim or pegfilgrastim) for at least 14 days; ^c.Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment.^d For patients with Gilbert's disease, total bilirubin should be </= 3 mg/dL (</= 51.3 µmol/L). ^e Approximately 15% of patients with RMC develop liver metastases ^1 ^f If creatinine is not <1.5×ULN, then calculate by Cockcroft-Gault methods or local institutional standard.
  10. INR and 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.
  11. Patients must have a measured ejection fraction of at least 45% as measured by either multigated acquisition (MUGA) scan, echocardiogram, stress test, or ventriculography.
  12. Patients with controlled brain metastases are allowed on protocol if they had solitary brain metastases that was surgically resected or treated with radiosurgery or Gamma knife, without recurrence or edema for 1 month (4 weeks).
  13. Female patients who: a.Are postmenopausal for at least 1 year before the screening visit, OR b.Are surgically sterile, OR c.Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of the study drug.
  14. Women must not be breastfeeding.
  15. WOCBP must agree to practice 2 effective method(s) of contraception, at the same time, from the time of enrollment for the duration of treatment with study drug (s) plus 5 half-lives of study drug (s) plus 30 days (duration of ovulatory cycle) for a total of 5 months post treatment completion, or agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception. a.Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an acceptable form of contraception for all study drugs.
  16. inclusion14 continued) Abstinence is only acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, profession of abstinence for entry into a clinical trial, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Subjects who choose complete abstinence are not required to use a second method of contraception, but female subjects must continue to have pregnancy tests. Acceptable alternate methods of highly effective contraception must be discussed in the event that the subject chooses to forego complete abstinence.
  17. Men who are sexually active with WOCBP, even if surgically sterilized (ie, status post-vasectomy), must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug (s) plus 5 half-lives of study drug (s) plus 90 days duration of sperm turnover) for a total of 5 months post-treatment completion.
  18. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However WOCBP must still undergo pregnancy testing as described in these sections.

Exclusion Criteria:

  1. 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.
  2. 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.
  3. 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.
  4. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
  5. Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBVsAg) test (regardless of HBV DNA levels or IgM 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.
  6. Patient has>/=Grade 3 peripheral neuropathy, or Grade 2 peripheral neuropathy with pain on clinical examination during the screening period.
  7. 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
  8. 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.
  9. Patients receiving any concomitant systemic therapy for renal cell cancer are excluded.
  10. 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.
  11. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as: a.Symptomatic congestive heart failure of New York heart Association Class III or IV. b.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. c.Severely impaired lung function as defined as 02 saturation that is 92% or less at rest on room air. d.Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN. e.Systemic fungal, bacterial, viral, or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement) despite appropriate antibiotics or other treatment. f.Known active or symptomatic viral hepatitis or chronic liver disease. Uncontrolled adrenal insufficiency.
  12. Patients must not have history of other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of ixazomib, gemcitabine, or doxorubicin, or that might affect the interpretation of the results of the study or render the subject at high risk from treatment complications
  13. Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases.
  14. Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods as defined above. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes. Hormonal contraceptives are not acceptable as a sole method of contraception.
  15. Failure to have fully recovered (ie, </=Grade 1 toxicity) from the reversible effects of prior chemotherapy.
  16. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03587662


Contacts
Contact: Pavlos Msaouel 713-792-2830 pmsaouel@mdanderson.org

Locations
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: M.       pmsaouel@mdanderson.org   
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
Principal Investigator: Pavlos Msaouel M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03587662     History of Changes
Other Study ID Numbers: 2018-0065
NCI-2018-01292 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2018-0065 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: July 16, 2018    Key Record Dates
Last Update Posted: August 27, 2018
Last Verified: August 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Renal Cell
Carcinoma, Medullary
Thyroid Neoplasms
Carcinoma, Neuroendocrine
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Ductal, Lobular, and Medullary
Neoplasms, Nerve Tissue
Endocrine Gland Neoplasms
Head and Neck Neoplasms
Endocrine System Diseases
Thyroid Diseases
Gemcitabine
Doxorubicin
Daunorubicin
Ixazomib
Liposomal doxorubicin
Glycine