Ixazomib + Chemotherapy for Kidney Cancer

Overseen By Pavlos Msaouel

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Proteasome inhibitors, Strong CYP3A inducers

Disqualifiers: HIV/AIDS, Hepatitis B/C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of drugs—ixazomib, gemcitabine, and doxorubicin—to evaluate their effectiveness against kidney cancer that has spread beyond the kidney. Ixazomib (also known as Ninlaro) aims to stop tumor growth by blocking certain cell growth enzymes, while gemcitabine and doxorubicin are chemotherapy drugs that kill cancer cells or prevent their spread. Individuals with metastatic kidney cancer who have previously tried other treatments might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have received anticancer therapies within 2 weeks before starting the trial, and certain medications like strong CYP3A inducers are not allowed within 14 days before the first dose of ixazomib. It's best to discuss your current medications with the trial team to ensure eligibility.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of ixazomib, gemcitabine, and doxorubicin has been studied for safety and effectiveness. In previous studies, most patients tolerated gemcitabine and doxorubicin well, experiencing no severe side effects.

While detailed safety information about ixazomib with these drugs is limited, the FDA has approved ixazomib for other uses, indicating its general safety when used correctly.

This is a phase 2 trial, meaning earlier trials have demonstrated the treatment's safety for testing on more people. This suggests a positive outlook for its overall safety in humans. Always consult a healthcare provider with any concerns about joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of ixazomib with chemotherapy for kidney cancer because it introduces a novel mechanism of action. Unlike standard treatments that primarily target cancer cells through traditional chemotherapy, ixazomib is a proteasome inhibitor, disrupting the protein degradation process crucial for cancer cell survival. This unique action could potentially enhance the effectiveness of chemotherapy agents like doxorubicin and gemcitabine, offering a more comprehensive attack on the cancer. This combined approach might improve treatment outcomes and offer new hope for patients with kidney cancer.

What evidence suggests that ixazomib, gemcitabine, and doxorubicin might be an effective treatment for kidney cancer?

In this trial, participants will receive a combination of ixazomib, gemcitabine, and doxorubicin. Research has shown that these drugs may effectively treat various cancers, including kidney cancer. Studies on ixazomib have found that patients can live without their cancer worsening for about 19 months, with 73% responding well when used with other drugs. When gemcitabine is combined with doxorubicin, about 21.4% of patients experienced tumor shrinkage, and 71.4% had stable disease. In a study on kidney cancer, patients treated with doxorubicin and gemcitabine lived for an average of 8.8 months. These treatments work in different ways to slow tumor growth, potentially improving outcomes for patients with advanced kidney cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Pavlos Msaouel

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with advanced or metastatic kidney cancer, including rare types like RMC and rhabdoid tumors. Eligible participants may have had prior treatments but must show disease progression. They need to be over 12 years old, in fairly good health (ECOG 0-2), and meet specific blood count and organ function criteria. Those with controlled brain metastases can join if they meet certain conditions.

Inclusion Criteria

Your heart pumps blood at a healthy rate, at least 45%.

It doesn't matter if my kidney tumor has been removed or is still there.

I am 12 or older and have both my agreement and my parents' consent.

Exclusion Criteria

I am not pregnant, breastfeeding, and if capable of having children, I am using effective birth control.

Severe and/or uncontrolled medical conditions or other conditions that could affect participation in the study

Known allergy to any of the study medications, their analogues, or excipients

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive ixazomib orally, gemcitabine intravenously over 90 minutes, and doxorubicin intravenously over 15-30 minutes on day 1. Treatment repeats every 14 days for up to 13 cycles.

26 weeks

Every 2 weeks

Maintenance

Patients receive ixazomib orally and gemcitabine intravenously over 90 minutes. Cycles repeat every 14 days for up to 2 years.

104 weeks

Every 2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion at 30 and 90 days, then every 3 months thereafter.

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Doxorubicin
• Gemcitabine
• Ixazomib

Trial Overview The study tests a combination of ixazomib (which blocks enzymes needed for cell growth) with chemotherapy drugs gemcitabine and doxorubicin on patients with locally advanced or metastatic kidney cancer. The goal is to see if this mix works better than current treatments at stopping tumor growth.

How Is the Trial Designed?

Group I: Treatment (ixazomib, gemcitabine, doxorubicin) Experimental Treatment 6 Interventions

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.

Doxorubicin is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Adriamycin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in European Union as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in Canada as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in Japan as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Chemotherapy, particularly with actinomycin-D and vincristine, has significantly improved survival rates for localized Wilms' tumor to over 80% and about 50% for metastatic cases, indicating its efficacy when combined with surgery and radiotherapy.

Initial studies suggest that combining actinomycin-D and vincristine may be more effective than using either drug alone, while the role of postoperative radiotherapy in fully resected tumors is still being evaluated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in the treatment of Wilms' tumor. Wolff, JA.[2019]

Dexrazoxane (DZR) significantly protects against doxorubicin (DOX)-induced kidney damage in rats, improving renal function and survival rates after DOX treatment.

DZR works by reducing oxidative stress, inhibiting apoptosis, and preventing fibrosis in the kidneys, suggesting it could be a valuable co-treatment to mitigate the nephrotoxic effects of DOX.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexrazoxane Alleviated Doxorubicin-Induced Nephropathy in Rats. Hu, H., Xie, C., Weng, Z., et al.[2022]

Paeonol (Pae) has been shown to protect against doxorubicin (Dox)-induced cardiotoxicity in both rat models and primary cardiomyocytes by enhancing mitochondrial fusion and restoring cardiac function.

The protective mechanism involves the PKCε-Stat3-Mfn2 signaling pathway, where Pae activates Stat3 to promote Mfn2-mediated mitochondrial fusion, without compromising the anticancer efficacy of Dox.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway. Ding, M., Shi, R., Fu, F., et al.[2023]

SC-33428, a new drug similar to doxorubicin, showed stronger bone marrow suppression in rats compared to doxorubicin, but had less harmful effects on the heart and kidneys.

The lower concentrations of SC-33428 in the body after administration suggest it may have a better safety profile than doxorubicin while maintaining similar effectiveness against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicological studies with a novel synthetic anthracycline, the bis-hydrazone bridged analog of 4-demethoxydaunorubicin (SC-33428). Zbinden, G., Beilstein, AK., Bachmann, E.[2013]

In a phase II study involving 12 patients with refractory renal cell cancer, pegylated-liposomal doxorubicin (Doxil) was administered with mild toxicities, primarily related to mucositis and hand-foot syndrome.

Despite the treatment being well-tolerated, no objective responses were observed in 11 evaluable patients, indicating that pegylated-liposomal doxorubicin does not demonstrate efficacy in this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of pegylated-liposomal doxorubicin (Doxil) in renal cell cancer. Skubitz, KM.[2019]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33591455/

Differential sensitivity of renal carcinoma cells to ... This study suggests that combination of doxorubicin with epigenetic therapeutics could potentially be beneficial in clinical treatment of renal cancer patients.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3566570/

A phase II trial of doxorubicin and gemcitabine in renal cell ... The median overall survival was 8.8 months, and the median progression-free survival was 3.5 months. We conclude that the combination of doxorubicin and ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1078143920304919

Outcomes of patients with metastatic renal cell carcinoma ... Among 7 snccRCC patients, only one (14.3%) achieved an objective partial response. At a median follow-up of 51.1 months, the median PFS was 4.9 months (95% CI: ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.6_suppl.324

Efficacy of gemcitabine plus doxorubicin (Gem + Dox) in ... The median overall survival (OS) from the start of Gem + Dox was 9.8 mo (95% CI 3.3-16.2) and the median OS from diagnosis was 18.6 mo (95% CI ...

5. urotoday.com urotoday.com/conference-highlights/esmo-2024/esmo-2024-kidney-cancer/154839-esmo-2024-non-clear-cell-rcc.html

ESMO 2024: Non-Clear Cell RCC More recently, cabozantinib was evaluated in 25 such patients and demonstrated a response rate of 35%, with a median progression-free survival ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03587662

NCT03587662 | Ixazomib, Gemcitabine, and Doxorubicin ... 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 ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12289336/

Efficacy and safety of gemcitabine plus doxorubicin in ... In this retrospective study, gemcitabine plus doxorubicin demonstrated clinical activity and was well tolerated in most patients, supporting its ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2019.37.7_suppl.TPS678

Phase II trial of ixazomib combined with gemcitabine and ... If both the ORR and DCR improve to 50% and 30%, respectively, then there is only a 3.5% chance of stopping early and a 93.1% chance of claiming ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT03587662?term=AREA%5BConditionSearch%5D(%22Neuroendocrine%20Carcinoma%22)%20AND%20AREA%5BInterventionSearch%5D(%22Gemcitabine%22)&rank=1

Study Details | Ixazomib, Gemcitabine, and Doxorubicin in ... A phase of research to describe clinical trials that focus on the safety of a drug. They are usually conducted with healthy volunteers, and the goal is to ...

10. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2018-0065.html

Phase II Trial of Ixazomib combined with Gemcitabine and ... 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 ...