Clinical Trials /

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

NCT03587662

Description:

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

Related Conditions:
  • Kidney Medullary Carcinoma
  • Rhabdoid Tumor
  • Unclassified Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trial of Ixazomib Combined With Gemcitabine and Doxorubicin in Patients With Renal Medullary Carcinoma
  • Official Title: Phase II Trial of Ixazomib Combined With Gemcitabine and Doxorubicin in Patients With Renal Medullary Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: 2018-0065
  • SECONDARY ID: NCI-2018-01292
  • SECONDARY ID: 2018-0065
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03587662

Conditions

  • Kidney Medullary Carcinoma
  • Stage III Renal Cell Cancer AJCC v8
  • Stage IV Renal Cell Cancer AJCC v8

Interventions

DrugSynonymsArms
DoxorubicinAdriablastin, Hydroxyl Daunorubicin, HydroxydaunorubicinTreatment (ixazomib, gemcitabine, doxorubicin)
GemcitabinedFdC, dFdCyd, DifluorodeoxycytidineTreatment (ixazomib, gemcitabine, doxorubicin)
IxazomibMLN-2238, MLN2238Treatment (ixazomib, gemcitabine, doxorubicin)

Purpose

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

Detailed Description

      Study Drug Administration:

      Each cycle is 14 days. Treatment will be given in 2 phases: Induction (Cycles 1-13) and
      Maintenance (Cycles 14 and beyond).

      On Day 1 of each cycle during Induction, you will take ixazomib 1 time by mouth, receive
      gemcitabine by vein over about 90 minutes, and receive doxorubicin by vein over 15-30
      minutes.

      On Day 1 of each cycle during Maintenance, you will take ixazomib 1 time by mouth and receive
      gemcitabine by vein over about 90 minutes. You will not receive doxorubicin.

      Gemcitabine and doxorubicin may be given through a catheter. A catheter is a sterile flexible
      tube that will be placed into a large vein while you are under anesthesia. Your doctor will
      explain this procedure to you in more detail, and you will be required to sign a separate
      consent form.

      You should shallow capsules whole, with water, and not chew, break, or open the capsules of
      ixazomib. Ixazomib should be taken on an empty stomach (no food or drink) at least 1 hour
      before or at least 2 hours after food. Each capsule should be swallowed separately with about
      8 ounces (1 cup) of water.

      After 13 cycles, if the tumor in your kidney is still present and the doctor thinks it is
      safe to do so, you will have surgery to remove as much of the tumor as possible. You will
      sign a separate consent form for this surgery which describes the procedure and risks in more
      detail.

      After 13 cycles and/or surgery (if you have it), you may continue to receive the study drugs
      for up to 2 years.

      Length of Study:

      You may receive the study drugs for up to 2 years, as long as the study doctor thinks it is
      in your best interest. You will not longer be able to take the study drugs** if the disease
      gets worse, if intolerable side effects occur, or if you are unable to follow study
      directions.

      Your participation on the study will be over after the follow-up visits.

      Study Visits:

      On Day 1 of each cycle:

        -  You will have a physical exam. vBlood (about 5 teaspoons) will be drawn for routine
           testing. During Cycles 1 and 2, you will have these blood draws performed 1 time every
           week.

        -  You will have an EKG and ECHO (Cycles 6 and 13). This may be repeated if the doctor
           thinks it is needed.

      At Weeks 6, 12, and then every 8 weeks after that (Weeks 20, 28, 36 and so on) during Year 1
      and then every 12 weeks after that:

        -  If the doctor thinks it is needed, you will have an MRI, CT scan, skeletal survey, or
           bone scan to check the status of the disease.

        -  Blood (about 1 teaspoon) and will be drawn for routine testing.

      End-of-Treatment Visit:

      About 30 and 90 days after your last dose of study drug(s):

        -  You will have a physical exam.

        -  You will have CT scan of the chest/abdomen or an MRI of abdomen/ pelvis

        -  If the doctor thinks it is needed and depending on why you stopped taking the study
           drug(s), you will have an MRI, CT scan, skeletal survey, or bone scan to check the
           status of the disease.

      Long-Term Follow-Up:

      You will be called by a member of the study staff every 3 months to ask how you are doing and
      if you have started any new anti-cancer treatments. This information may be collected from
      your medical record instead. If called, this phone call should take about 5-10 minutes. These
      calls will stop if the disease gets worse or you start a new anti-cancer therapy.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (ixazomib, gemcitabine, doxorubicin)ExperimentalINDUCTION: 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.
  • Doxorubicin
  • Gemcitabine
  • Ixazomib

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response (complete response or partial response) assessed by Response Evaluation Criteria in Solid (RECIST) 1.1
Time Frame:Up to 2 years
Safety Issue:
Description:

Secondary Outcome Measures

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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated