Mitotane +/- Cisplatin and Etoposide for Adrenal Cancer

Recruiting at 35 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether the drug mitotane is more effective alone or combined with two other chemotherapy drugs, cisplatin and etoposide, in preventing adrenal cancer from returning after surgery. Adrenocortical cancer can regrow due to a hormone called cortisol, and mitotane helps reduce this hormone. Participants must have undergone adrenal cancer surgery within the past 90 days and be at high risk of cancer recurrence. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants an opportunity to contribute to potentially groundbreaking treatment advancements.

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.

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

Research has shown that mitotane often treats adrenocortical carcinoma, a rare cancer of the adrenal glands. It may cause adrenal insufficiency, potentially lowering hormone production in the adrenal glands. Patients may require regular hormone level checks.

When combined with cisplatin and etoposide, mitotane treats more advanced cancer cases. This combination stops cancer cells from growing. However, each drug can cause side effects. Cisplatin may cause nausea and kidney problems, while etoposide can lower blood cell counts, leading to tiredness or a higher risk of infections.

As this trial is in a late phase, there is already some confidence in the safety of these treatments. However, participants should be aware of possible side effects and discuss them with their doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for adrenal cancer, Mitotane is unique because it specifically targets the adrenal cortex, where these tumors originate. Researchers are excited about combining Mitotane with Cisplatin and Etoposide since this approach not only leverages Mitotane's targeted action but also adds the potency of chemotherapy drugs that can attack cancer cells more broadly. This combination could enhance treatment effectiveness and possibly improve patient outcomes by tackling the cancer from multiple angles.

What evidence suggests that this trial's treatments could be effective for adrenocortical cancer?

Research has shown that mitotane can help treat adrenocortical carcinoma, a challenging cancer of the adrenal glands. Patients taking mitotane have experienced a longer period without cancer recurrence—about 42 months—compared to just 10 months for those not taking it. Mitotane lowers cortisol levels, which can help slow tumor growth.

In this trial, one group of participants will receive mitotane alone, while another group will receive a combination of mitotane with cisplatin and etoposide. Combining mitotane with these chemotherapy drugs has produced mixed results. While this combination might help fight the cancer, it can also cause moderate to severe side effects. Researchers continue to study whether this combination is more effective than using mitotane alone. ^{1 5 6 7 8}

Who Is on the Research Team?

Mouhammed A. Habra

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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 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 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 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 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 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]

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]

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]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11379655/

A review of mitotane in the management of adrenocortical ...

Patients with progression had a lower time in the target range (TTR) of plasma mitotane and an unfavorable outcome. Death occurred in 76.2% of ...

2.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/11494911/

Therapy of the adrenocortical carcinoma with Lysodren (o,p

Our data confirm that the efficacy of a therapy with o,p'-DDD as well as the risk to develop intolerable side effects depend on the serum levels of o,p'-DDD ...

3.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa063360

Adjuvant Mitotane Treatment for Adrenocortical Carcinoma

The median recurrence-free survival was 42 months in the mitotane group, 10 months in control group 1 (P<0.001), and 25 months in control group ...

4.

academic.oup.com

academic.oup.com/jcem/article/105/2/407/5581636

The Efficacy of Mitotane in Human Primary Adrenocortical ...

Mitotane inhibited cortisol production with a mean EC 50 of 1.4 μM (95% CI, 0.9–2.1), which was considerably lower than the EC 50 on cell growth.

5.

link.springer.com

link.springer.com/article/10.1007/s40267-022-00958-y

Mitotane in adrenocortical carcinoma: a profile of its use

Mitotane (Lysodren) has a central role in the systemic treatment of adrenocortical carcinoma (ACC), a rare and aggressive cancer of the adrenal glands.

6.

accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/label/2009/016885s023lbl.pdf

LYSODREN - accessdata.fda.gov

Data in adrenal carcinoma patients indicate that about 40% of oral LYSODREN is absorbed and approximately 10% of administered dose is recovered in the urine as ...

7.

accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/label/2024/016885Orig1s032lbl.pdf

Lysodren - accessdata.fda.gov

LYSODREN can cause adrenal insufficiency or worsen existing adrenal insufficiency in patients with adrenocortical carcinoma. Monitor for both glucocorticoid and ...

8.

go.drugbank.com

go.drugbank.com/drugs/DB00648

Mitotane: Uses, Interactions, Mechanism of Action

Mitotane is indicated for the treatment of inoperable, functional or nonfunctional, adrenocortical carcinoma.