Mitotane +/- Cisplatin and Etoposide for Adrenal Cancer

Recruiting at 8 trial locations

Overseen By Mouhammed Habra

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: M.D. Anderson Cancer Center

Must be taking: Mitotane

Disqualifiers: Metastatic disease, Renal insufficiency, Liver insufficiency, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 21

Duration: Up to 2 years

240 Participants Needed

Trial Summary

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

The trial protocol does not specify if you need to stop taking your current medications. However, since the trial involves chemotherapy drugs, it's possible that some medications might need to be adjusted. Please consult with the trial coordinators or your doctor for specific guidance.

What data supports the idea that Mitotane +/- Cisplatin and Etoposide for Adrenal Cancer is an effective drug?

The available research does not provide specific data on the effectiveness of Mitotane +/- Cisplatin and Etoposide for Adrenal Cancer. The studies mentioned focus on other conditions, such as non-Hodgkin lymphoma, ovarian cancer, and Ewing sarcoma, using similar drugs. For example, one study showed a 55% response rate in non-Hodgkin lymphoma patients using a combination that included etoposide. Another study reported responses in ovarian cancer patients who had not responded to previous treatments. However, these results cannot be directly applied to adrenal cancer without specific research on that condition. ^{1 2 3 4 5}

What safety data is available for Mitotane, Cisplatin, and Etoposide treatment?

The safety data for the combination of Cisplatin and Etoposide, sometimes with Mitotane, shows significant toxicities. In a study with advanced non-small-cell lung cancer patients, high-dose Cisplatin and Etoposide caused major myelosuppression, with 26% developing neutropenic fever, and one patient died due to toxicity. Nonhematologic toxicities included azotemia, peripheral neuropathy, nausea, vomiting, and hearing loss, which were transient and modest. Another study in Hodgkin's disease patients reported significant leukopenia, thrombocytopenia, and severe nausea and vomiting with the Cisplatin and Etoposide combination. These findings suggest that while the combination can be active, it is associated with considerable toxicity. ^{3 4 6 7 8}

Is the drug Mitotane a promising treatment for adrenal cancer?

The information provided does not directly address the effectiveness of Mitotane for adrenal cancer. The articles focus on other drugs and treatments for different types of cancer. Therefore, based on the given information, we cannot determine if Mitotane is a promising treatment for adrenal cancer. ^{2 8 9 10 11}

What is the purpose of this trial?

This phase III trial studies how well mitotane alone works compared to mitotane with cisplatin and etoposide when given after surgery in treating patients with adrenocortical cancer that has a high risk of coming back (recurrence). Cortisol can cause the growth of adrenocortical tumor cells. Antihormone therapy, such as mitotane, may lessen the amount of cortisol made by the body. Drugs used in chemotherapy, such as cisplatin and etoposide, 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. It is not yet known whether mitotane alone or mitotane with cisplatin and etoposide after surgery works better in treating patients with adrenocortical carcinoma.

Research Team

Mouhammed A. Habra

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with Stage I-III adrenocortical cancer who've had surgery to remove the tumor. They should be at high risk of the cancer returning, have a good performance status (able to carry out daily activities), and no recent other cancers or severe health issues. Pregnant or breastfeeding individuals can't join, nor those with kidney failure, heart failure, liver problems, bone marrow suppression, neuropathy, or prior ACC treatments.

Inclusion Criteria

I had adrenal cancer surgery recently and my cancer is at a high risk of coming back.

Be able to comply with the protocol procedures

Provide written informed consent

Exclusion Criteria

My platelet count is below 100,000/mm^3.

There is a strong chance that the cancer has spread to other parts of the body based on imaging tests.

Pregnancy or breast feeding

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive mitotane daily for 21-day cycles, with or without cisplatin and etoposide for up to 4 cycles

Up to 2 years

Every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 6 months

Treatment Details

Interventions

• Cisplatin
• Etoposide
• Mitotane

Trial Overview The study compares two approaches after surgery: one group receives only mitotane (a drug that reduces cortisol production by the body) while another group gets mitotane combined with chemotherapy drugs cisplatin and etoposide. The goal is to see which method is more effective in preventing cancer recurrence.

Participant Groups

Group I: Arm B (mitotane, etoposide, cisplatin) Experimental Treatment 4 Interventions

Patients receive mitotane as in Arm A. Patients also receive cisplatin IV over 2 hours on day 1 and etoposide IV over 2 hours on days 1-3. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Arm A (mitotane) Experimental Treatment 2 Interventions

Patients receive mitotane PO daily on days 1-21. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity.

Mitotane is already approved in United States, European Union for the following indications:

Approved in United States as Lysodren for:

• Adrenocortical carcinoma

Approved in European Union as Lysodren for:

• Adrenocortical carcinoma
• Cushing's syndrome

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+

Assistance Publique - Hôpitaux de Paris

Collaborator

Trials

3,369

Recruited

57,400,000+

University Hospital Wurzburg

Collaborator

University Hospital Munich

Collaborator

Trials

20

Recruited

13,800+

Skanes Universitetssjukhus

Collaborator

Findings from Research

In a study of 29 patients with relapsing or refractory high-grade malignant non-Hodgkin lymphoma (NHL), the ENAP chemotherapy regimen showed a promising overall response rate of 55%.

When ENAP was used as a first-line treatment in 45 previously untreated NHL patients, it resulted in a complete remission rate of 27% and a partial remission rate of 73% after just one course, indicating its effectiveness as both a first-line and salvage treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitoxantrone, etoposide, cytarabine and prednisone as salvage therapy for refractory non-Hodgkin lymphoma (NHL) and alternated with CHOP in previously untreated patients with NHL. Merk, K., Ideström, K., Johansson, B., et al.[2019]

In a phase II trial involving 31 patients with refractory ovarian carcinoma, intraperitoneal mitoxantrone showed efficacy, particularly in patients with small tumors (≤1 cm), where 33% had documented responses, including some who previously failed other treatments.

Despite its effectiveness, the treatment caused significant local toxicity, with 74% of patients requiring pain relief and several experiencing severe complications like bowel obstruction, leading to the conclusion that this regimen is not suitable for standard clinical practice without further modifications to reduce toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of intraperitoneal mitoxantrone in the management of refractory ovarian cancer. Markman, M., George, M., Hakes, T., et al.[2017]

In a study of 58 patients with relapsing/refractory Ewing sarcoma, low-dose oral etoposide (VP-16) demonstrated efficacy, with 11 out of 46 evaluable patients showing a response, including one complete remission and nine partial remissions, lasting an average of 8 months.

The treatment was associated with manageable toxicity, with 15% of cycles showing severe hematologic toxicity, and a noted risk of secondary leukemia, consistent with existing literature, suggesting that low-dose VP-16 could be a viable option in palliative care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral etoposide in relapsed or refractory Ewing sarcoma: a monoinstitutional experience in children and adolescents. Podda, MG., Luksch, R., Puma, N., et al.[2017]

In a study of 107 patients with advanced Ewing sarcoma, those treated with the combination of etoposide and carboplatin had a median overall survival of 23 months and a better progression-free survival of 14.5 months compared to 6.3 months for those treated with etoposide and cisplatin.

The findings suggest that the etoposide and carboplatin combination may be more effective than etoposide and cisplatin, warranting further investigation in prospective studies for patients with relapsed Ewing sarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etoposide and carbo-or cisplatin combination therapy in refractory or relapsed Ewing sarcoma: a large retrospective study. van Maldegem, AM., Benson, C., Rutkowski, P., et al.[2022]

In two cases of recurrent ovarian adenocarcinoma that did not respond to standard chemotherapy, a salvage therapy using cis-platinum and etoposide resulted in a complete response.

The treatment regimen included cis-platinum at a dose of 120 mg/m2 every 3 weeks and etoposide at 200 mg weekly, demonstrating a potential alternative for patients resistant to conventional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment for recurrent ovarian cancer. A report of 2 cases. Maxwell, AM., Jordaan, JP.[2014]

In a study of 46 patients with metastatic non-small-cell lung cancer, the combination of high-dose cisplatin, etoposide, and mitomycin resulted in a low response rate, with only 10% achieving a partial response and no complete responses observed.

The treatment was associated with significant toxicity, particularly myelosuppression, leading to severe neutropenic fever in 26% of patients, indicating that this regimen is relatively toxic and not effective enough to warrant further evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of combination therapy with high-dose cisplatin, etoposide, and mitomycin in patients with advanced non-small-cell lung cancer. Shin, DM., Dhingra, HM., Lee, JS., et al.[2019]

Ewing sarcoma (EWS) cells are particularly sensitive to PARP inhibitors (PARPis) due to their defects in DNA break repair, showing 10- to 1,000-fold increased cytotoxicity when combined with DNA-damaging agents like irinotecan or temozolomide.

In a mouse model of EWS, the combination of low-dose irinotecan with PARPis resulted in complete and durable responses in over 80% of the subjects, indicating a promising treatment strategy for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the DNA repair pathway in Ewing sarcoma. Stewart, E., Goshorn, R., Bradley, C., et al.[2022]

In a phase II study involving 27 patients with refractory Hodgkin's disease, the combination of etoposide and cis-platin resulted in an overall response rate of 36%, with 18% achieving complete responses, indicating some efficacy in this difficult-to-treat population.

However, the treatment was associated with significant toxicity, including severe leukopenia in 45% of patients and thrombocytopenia in 50%, highlighting the need for careful monitoring and consideration of side effects in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of etoposide and cis-diaminodichloro-platinum in patients with refractory and relapsed Hodgkin's disease: Cancer and Leukemia Group B (CALGB) Study 8353. Rybak, ME., McCarroll, K., Kaplan, RJ., et al.[2019]

In a study of 36 patients with small residual ovarian cancer, treatment with intraperitoneal cisplatin and intravenous etoposide resulted in a pathological complete response in 7 patients and a median progression-free survival of 11 months, indicating some efficacy.

While the treatment had manageable side effects, including significant leucopenia and thrombocytopenia, the overall efficacy was limited, particularly with a high rate of intraperitoneal relapses, suggesting that local treatment may not be sufficient.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of intraperitoneal cisplatin plus systemic etoposide as second-line treatment in patients with small volume residual ovarian cancer. de Jong, RS., Willemse, PH., Boonstra, H., et al.[2019]

In a retrospective study of 8 patients with high-grade neuroendocrine tumors of the colon and rectum treated with cisplatin and etoposide, there was a notable response rate, with one complete response and four partial responses observed.

The median progression-free survival was 4.5 months and the median overall survival was 9.5 months, indicating that while the treatment can be effective, the benefits are often short-lived, with survival typically lasting less than a year.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line cisplatin plus etoposide in high-grade metastatic neuroendocrine tumors of colon and rectum (MCRC NET): review of 8 cases. Patta, A., Fakih, M.[2016]

Mitozantrone (MTZ) showed limited effectiveness as a single-dose treatment for acute leukaemia, but a 5-day regimen resulted in a 24% complete remission rate in patients with relapsed or refractory disease.

In a phase III study, combining MTZ with a 7-day infusion of cytosine arabinoside (Ara-C) led to a remarkable 68% of patients becoming leukaemia-free, indicating a strong potential for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of mitozantrone in the treatment of acute leukaemia. Prentice, HG.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Mitoxantrone, etoposide, cytarabine and prednisone as salvage therapy for refractory non-Hodgkin lymphoma (NHL) and alternated with CHOP in previously untreated patients with NHL. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Phase II trial of intraperitoneal mitoxantrone in the management of refractory ovarian cancer. [2017]

3. United States pubmed.ncbi.nlm.nih.gov

Oral etoposide in relapsed or refractory Ewing sarcoma: a monoinstitutional experience in children and adolescents. [2017]

4. United States pubmed.ncbi.nlm.nih.gov

Etoposide and carbo-or cisplatin combination therapy in refractory or relapsed Ewing sarcoma: a large retrospective study. [2022]

5. South Africa pubmed.ncbi.nlm.nih.gov

Treatment for recurrent ovarian cancer. A report of 2 cases. [2014]

6. United States pubmed.ncbi.nlm.nih.gov

Phase II study of combination therapy with high-dose cisplatin, etoposide, and mitomycin in patients with advanced non-small-cell lung cancer. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Targeting the DNA repair pathway in Ewing sarcoma. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Phase II trial of etoposide and cis-diaminodichloro-platinum in patients with refractory and relapsed Hodgkin's disease: Cancer and Leukemia Group B (CALGB) Study 8353. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Phase II study of intraperitoneal cisplatin plus systemic etoposide as second-line treatment in patients with small volume residual ovarian cancer. [2019]

10. Greece pubmed.ncbi.nlm.nih.gov

First-line cisplatin plus etoposide in high-grade metastatic neuroendocrine tumors of colon and rectum (MCRC NET): review of 8 cases. [2016]

11. Switzerland pubmed.ncbi.nlm.nih.gov

The role of mitozantrone in the treatment of acute leukaemia. [2018]