Neoplasms

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Adrenocortical Carcinoma

Neoplasms, Glandular and Epithelial

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Adrenal Cortex Neoplasms

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Iressa (ZD1839)

Vivek Samnotra, MD

The use of Iressa will result in a greater than 20% response rate in patients with nonresectable adrenocortical cancer who have previously been treated with one other form of systemic therapy (either Mitotane or chemotherapy).

Adrenocortical carcinoma is a rare cancer with an incidence of 1.5 to 2 per million people in the United States. Surgery is the only potentially curative option. Current systemic therapy, either Mitotane or chemotherapy, typically gives response rates of 20% or less. This study is designed to see if the newer targeted therapy, Iressa, may be of benefit for patients with this fatal disease.

Patients with nonresectable adrenocortical cancer who have progressed on at least one other form of systemic therapy (Mitotane or chemotherapy) will be given Iressa 250 mg by mouth daily until disease progression. This is a standard two-stage Phase II clinical trial. Eighteen patients with measurable disease will be enrolled in the first stage. If there is at least one responder, then an additional nine patients with measurable disease will be enrolled for a total of 27 patients with measurable disease. Up to six patients without measurable disease may be enrolled at any point in this study. Iressa will be provided free for all study participants.

Phase II Trial of ZD1839 (Iressa) in Patients With Nonresectable Adrenocortical Carcinoma (ACC)

A Phase II Trial of ZD1839 (Iressa) in Patients With Nonresectable Adrenocortical Carcinoma (ACC)

AstraZeneca

M.D. Anderson Cancer Center

Dana-Farber Cancer Institute

Kentuckiana Cancer Institute

Dartmouth-Hitchcock Medical Center

Anti-Infective Agents

Etoposide

Doxorubicin

Liposomal doxorubicin

Vincristine

Etoposide phosphate

Mitotane

polysaccharide-K

Surgical resection can be performed at the time of study entry, when patients have a mixed response, or if their tumors respond to chemotherapy.

Surgical resection will be followed by chemotherapy with 2 grams oral dose daily of mitotane on cycle 1, day 1, 6 mg/m\^2 continuous intravenous infusion doxorubicin over 96 hours days 1-4, 0.18 mg/m\^2 continuous intravenous infusion vincristine over 96 hours days 1-4, and 36 mg/m\^2 continuous intravenous infusion etoposide over 96 hours days 1-4, and 150 mg tariquidar through central venous catheter over 30 minutes on days 1 and 3.

XR9576 (Tariquidar)

Antonio Fojo, M.D.

This study will examine the safety and effectiveness of treating adrenocortical cancer with combination chemotherapy using doxorubicin, vincristine, and etoposide in addition to the drugs mitotane and tariquidar and, when possible, surgery. Adrenocortical cancer cells have a large amount of a protein called P-glycoprotein that "pumps" anti-cancer drugs out of the cells, decreasing their effectiveness. Continuous infusions of doxorubicin, vincristine, and etoposide may improve chemotherapy results by blocking the P-glycoprotein pump, as may use of tariquidar, an experimental drug that is known to block the P-glycoprotein pump.

Patients 18 years of age and older with adrenocortical cancer that has recurred, spread, or cannot be treated surgically may be eligible for this study. Candidates will be screened with a medical history and physical examination; review of pathology slides; blood tests; electrocardiogram (EKG); imaging tests, including computed tomography (CT) of the chest, abdomen and pelvis; chest x-ray; and possibly a bone scan or other imaging tests needed to evaluate the cancer, urine studies, and an echocardiogram. Also, a biopsy (removal of a small sample of tumor tissue) may be required if a specimen is not available to confirm the cancer.

Participants will undergo the following tests and procedures:

* Tumor biopsy. Before starting chemotherapy, a small piece of tumor is removed to study the P-glycoprotein pump and to determine the tumor genetics.
* Blood draw. Blood is drawn before treatment begins to establish baseline levels for future blood tests.
* Central venous catheter placement. A specially trained physician places a plastic tube into a major vein in the chest. The tube is used to give the study drugs and other medications and to withdraw blood samples. It can stay in the body for months or be removed after each treatment is completed. The tube placement is done under a local anesthetic in the radiology department or operating room.
* Chemotherapy. Treatment cycles are 21 days. Doxorubicin, vincristine, and etoposide are given through the central venous catheter by an infusion pump continuously over 96 hours starting day 1 of each cycle. The dose of these drugs may be increased or decreased from cycle to cycle, based on side effects. Mitotane is given in pill form starting day 1 of cycle 1 and is taken every day throughout the entire study. The mitotane dose is gradually increased as long as the side effects are tolerable. Tariquidar is given through the central venous catheter as a 30-minute infusion on days 1 and 3 of every cycle. The tariquidar dose remains the same throughout the study. Treatment will continue for two cycles after all the cancer is gone, or until surgery is done to remove some or all of the remaining cancer, or, if surgery is not an option, until the cancer has grown to where it is defined as progressive disease.
* Nuclear scans. A nuclear scan is done before treatment begins and again on day 1 or day 3 of the first treatment cycle after administration of tariquidar to evaluate the P glycoprotein response to treatment.
* Computed tomography (CT) scans. These scans are done every two treatment cycles to follow disease progress.
* Surgery. Surgery to remove areas of cancer may be considered at any point during the study (including before beginning treatment), if it is deemed beneficial. Treatment with the study drugs will begin or resume after surgery. The length of treatment will depend on the response to treatment before the surgery and on whether there is any cancer remaining after the surgery.

Adrenocortical cancer (ACC) is a rare tumor that is optimally treated with surgical resection. However, many patients present with unresectable disease and relapses are common after surgical resection creating a need for more effective systemic therapies. Several investigators have reported responses to a variety of chemotherapy agents, without a clear improvement in overall survival. A possible explanation for these disappointing results is the high levels of expression of P-glycoprotein (Pgp) seen in a majority of adrenocortical cancers. Pgp, a membrane protein that can function as a drug efflux pump lowering the intracellular concentrations of various drugs, has been implicated as a mechanism of drug resistance.

A prior National Cancer Institute (NCI) study (referred to as MAVE) tried to improve response rates by using a combined modality approach with chemotherapy and surgery. Prior in vitro studies had shown that mitotane inhibited Pgp and that continuous exposure to doxorubicin and vincristine was more effective at overcoming Pgp-mediated resistance than the same drugs given on an intermittent schedule. The MAVE study used daily oral mitotane with infusional doxorubicin, vincristine, and etoposide prior to tumor resection in patients with resectable or potentially resectable tumors. The results showed an overall response rate of 19% (including minor responses), and an overall median survival of 13.5 months. These results were similar to those reported with previous regimens in adrenocortical cancer (ACC). A possible explanation for the failure to achieve a higher response rate may be that mitotane was unable to inhibit Pgp. Although the serum levels of mitotane achieved in patients had been shown to block Pgp in vitro, inhibition of Pgp in patients was not accomplished, as documented by a validated surrogate assay using Pgp-expressing CD56+ cells and the Pgp substrate, rhodamine. Thus the question of whether Pgp inhibition would improve response rates remains unanswered.

This trial will attempt to answer the latter question by using an agent, tariquidar (XR9576), which has been proven to inhibit Pgp in humans with minimal toxicity alone or in combination with chemotherapy. Tariquidar will be used with the regimen from the prior MAVE study in an effort to improve response rates and overall survival in patients with ACC whose options at this time are limited.

Surgery Plus Chemotherapy (Doxorubicin, Vincristine and Etoposide), Mitotane, and Tariquidar to Treat Adrenocortical Cancer

A Study of Combination Chemotherapy & Surgical Resection in the Tx of Adrenocortical Cancer: Mitotane & Continuous Infusion Doxorubicin, Vincristine & Etoposide w/the P-glycoprotein Antagonist, Tariquidar (XR9576), Before & After Surgical Resection

Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete response is defined as the disappearance of all signs and symptoms of tumor for a period of at least 4 weeks. Partial response is defined as at least a 30% decrease in the sum of the longest diameter of all measured lesions lasting for a period of 4 weeks.

Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

National Cancer Institute (NCI)

Antonio Fojo, M.D./National Cancer Institute

Surgical resection can be performed at the time of study entry, when patients have a mixed response, or if their tumors respond to chemotherapy.

Surgical resection will be followed by chemotherapy with 2 grams oral dose daily of mitotane on cycle 1, day 1, 6 mg/m\^2 continuous intravenous infusion doxorubicin over 96 hours days 1-4, 0.18 mg/m2 continuous intravenous infusion vincristine over 96 hours days 1-4, and 36 mg/m\^2 continuous intravenous infusion etoposide over 96 hours days 1-4, and 150 mg tariquidar through central venous catheter over 30 minutes on days 1 and 3.

Surgery Plus Chemothrapy

Age, Categorical

Age Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Complete Response

Partial Response

Surgery Plus Chemotherapy

Percentage of Participants With a Partial or Complete Response

Number of Participants With Adverse Events

Overall Study

Symptoms and General Pathology

Recurrence

Axitinib

Aggressive cancer that starts in the adrenal gland located at the top of the kidneys.

5 mg tab orally twice a day with food every 28 days

Antonio T Fojo, M.D.

Background:

- Adrenocortical carcinoma is an aggressive cancer that starts in the adrenal gland at the top of the kidneys. It has a low survival rate if standard treatment options are not effective. Axitinib is an experimental drug that is being studied to determine if it can stop tumors from growing or make them smaller. Researchers are interested in investigating axitinib in individuals with aggressive or otherwise untreatable adrenocortical cancer.

Objectives:

- To evaluate the effectiveness of axitinib in individuals who have adrenocortical cancer that is inoperable and has not responded to standard treatments.

Eligibility:

- Individuals at least 18 years of age who have been diagnosed with adrenocortical cancer that has not responded to standard treatments.

Design:

* Participants will be screened with a full physical examination and medical history, as well as tumor imaging studies.
* Participants may have a tumor biopsy prior to starting axitinib.
* All participants will receive axitinib to take twice a day with food for 28 days (1 cycle). Participants should not drink grapefruit juice or smoke cigarettes while participating in this study.
* After the first cycle, the dose may be increased and additional cycles will be given if the treatment has not had serious side effects.
* Participants will have regular examinations while taking axitinib, including blood samples and tumor imaging studies to determine if the tumor has stopped growing. Blood pressure levels will be carefully monitored during treatment to evaluate potential risk for high blood pressure.
* Participants may have a second tumor biopsy 20 to 30 days after treatment begins.
* Treatment will continue as directed by the study researchers.

Background:

* The response rates of recurrent, metastatic and unresectable adrenocortical cancer (ACC) to mitotane, doxorubicin, etoposide, and cisplatin are low and underscore the need for more effective systemic therapies.
* VEGF expression and evidence of angiogenesis has been found in many ACCs, so it is plausible that interfering with vascular endothelial growth factor(VEGF) signaling may result in anti-tumor activity in patients with ACC.
* Axitinib (AG-013736) is an oral, potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. Pre-clinical data suggests that the anti-tumor activity of axitinib may result from its anti-angiogenic activity and that this is reversible when treatment is discontinued.
* Given the known clinical safety and efficacy of axitinib, an assessment of its activity in ACC and its impact on the VEGF pathway in ACC could provide valuable information.

Objectives:

* Determine the response rate of axitinib (AG-013736) in recurrent, metastatic, or primary unresectable ACC
* Determine the progression-free survival
* Explore the relationship of potential biological markers of axitinib activity with clinical outcomes.
* Explore the pharmacogenetic analyses of drug metabolism and transport proteins through germline deoxyribonucleic acid (DNA) examination.

Eligibility:

* Adults with pathologic confirmation of ACC by the Laboratory of Pathology, National Cancer Institute (NCI)
* Diagnosis of recurrent, metastatic, or primary unresectable ACC
* Measurable disease at presentation
* Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
* Patients must not have received prior therapy with a tyrosine kinase (TK) inhibitor

Design:

* Phase II, open label, non-randomized trial
* Patients with recurrent, metastatic, or primary unresectable ACC will be given in eight weeks cycles with BID dosing of axitinib (AG-013736).
* Patients will be evaluated for response every eight weeks using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
* Tumor biopsies are not mandatory but every attempt will be made to obtain these from patients prior to starting axitinib and again 20-30 days after treatment has begun.
* Approximately 40 patients will be needed to achieve the objectives of the trial.

Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-Pathway in Metastatic, Recurrent or Primary Unresectable Adrenocortical Cancer

Response was defined by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is a disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameter. Progressive disease (PD) is a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: the appearance of one or more new lesions is also considered progression). Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking s reference the smallest sum diameters while on study.

Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse events module.

Pfizer

Aggressive cancer that starts in the adrenal gland located at the top of the kidneys.

Axitinib : 5 mg tab orally twice a day with food every 28 days

Dr. Tito Fojo

Progression

Stable Disease

Response Rate (RR) of Axitinib Administered Daily, in Patients With Recurrent, Metastatic, or Primary Unresectable Adrenocortical Cancer (ACC)

Skin and Connective Tissue Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Diseases and Abnormalities at or Before Birth

Nervous System Diseases

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Neoplasms, Germ Cell and Embryonal

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Neuroectodermal Tumors, Primitive, Peripheral

Neoplasms, Neuroepithelial

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Neoplasms, Connective Tissue

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Cyclophosphamide

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Mechlorethamine

Nitrogen Mustard Compounds

Mesna

Alkylating Agents

2'-deoxyadenosine

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

During the treatment phase, the participant receives an infusion of the B7-H3-CAR T cells that were made in the Collection and Manufacturing Phase. Chemotherapy is given for several days prior to the cellular infusion. Patients are then monitored for possible side effects, as well as effects of the treatment on their cancer.

Fludarabine phosphate is a synthetic purine nucleoside analog. It acts by inhibiting DNA polymerase, ribonucleotide reductase and DNA primase by competing with the physiologic substrate, deoxyadenosine triphosphate, resulting in inhibition of DNA synthesis. Intravenous

Cyclophosphamide is a nitrogen mustard derivative. It acts as an alkylating agent that causes cross-linking of DNA strands by binding with nucleic acids and other intracellular structures, thus interfering with the normal function of DNA. Intravenous

Mesna is a synthetic sulfhydryl (thiol) compound. Mesna contains free sulfhydryl groups that interact chemically with urotoxic metabolites of oxaza-phosphorine derivatives such as cyclophosphamide and ifosfamide

MESNA

The study participant will receive B7-H3-CAR T cells by vein, through either an IV or a central line.

B7-H3 CAR T cells

Chris DeRenzo, MD

3CAR is being done to investigate an immunotherapy for patients with solid tumors. It is a Phase I clinical trial evaluating the use of autologous T cells genetically engineered to express B7-H3-CARs for patients ≤ 21 years old, with relapsed/refractory B7-H3+ solid tumors. This study will evaluate the safety and maximum tolerated dose of B7-H3-CAR T cells.The purpose of this study is to find the maximum (highest) dose of B7-H3-CAR T cells that are safe to give to patients with B7-H3-positive solid tumors.

Primary objective

To determine the safety of one intravenous infusion of autologous, B7-H3-CAR T cells in patients (≤ 21 years) with recurrent/refractory B7-H3+ solid tumors after lymphodepleting chemotherapy

Secondary objective

To evaluate the antitumor activity of B7-H3-CAR T cells

Exploratory objectives

* To evaluate the tumor environment after treatment with B7-H3-CAR T cells
* To assess the immunophenotype, clonal structure and endogenous repertoire of B7-H3-CAR T cells and unmodified T cells
* To characterize the cytokine profile in the peripheral blood after treatment with B7-H3-CAR T cells

Treatment will include a single infusion of B7-H3-CAR T cells after lymphodepleting chemotherapy, with dosing based on the number of CAR+ T cells and patient weight. The study will evaluate the safety and maximum tolerated dose (MTD) of B7-H3-CAR T cells, using a standard 3+3 study design and a 6-week evaluation period. The total study duration will be 1 year, at which point patients will enroll on our existing institutional long-term follow-up protocol.

B7-H3-Specific Chimeric Antigen Receptor Autologous T-Cell Therapy for Pediatric Patients With Solid Tumors (3CAR)

A phase I design to determine the maximum tolerated dose (MTD) of autologous, B7-H3-CAR T cells. Four dose levels (3x10\^5/kg, 1x10\^6/kg, 3x10\^6/kg, and 1x10\^7/kg) will be evaluated.

The number of patients with objective responses (complete response (CR) + partial response (PR)) determined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

St. Jude Children's Research Hospital

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase II Trial of ZD1839 (Iressa) in Patients With Nonresectable Adrenocortical Carcinoma (ACC)	NCT00215202	Nonresectable A...	Iressa (ZD1839)	18 Years -	Dartmouth-Hitchcock Medical Center
Surgery Plus Chemotherapy (Doxorubicin, Vincristine and Etoposide), Mitotane, and Tariquidar to Treat Adrenocortical Cancer	NCT00071058	Adrenal Cortex ...	XR9576 (Tariqui...	18 Years -	National Institutes of Health Clinical Center (CC)
Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-Pathway in Metastatic, Recurrent or Primary Unresectable Adrenocortical Cancer	NCT01255137	Adrenal Cortex ...	Axitinib	18 Years - 80 Years	National Institutes of Health Clinical Center (CC)
Surgery Plus Chemotherapy (Doxorubicin, Vincristine and Etoposide), Mitotane, and Tariquidar to Treat Adrenocortical Cancer	NCT00071058	Adrenal Cortex ...	XR9576 (Tariqui...	18 Years -	National Institutes of Health Clinical Center (CC)
B7-H3-Specific Chimeric Antigen Receptor Autologous T-Cell Therapy for Pediatric Patients With Solid Tumors (3CAR)	NCT04897321	Pediatric Solid... Osteosarcoma Rhabdomyosarcom... Neuroblastoma Ewing Sarcoma Wilms Tumor Adrenocortical ... Desmoplastic Sm... Germ Cell Cance... Rhabdoid Tumor Clear Cell Sarc... Hepatoblastoma Melanoma Carcinoma Malignant Perip... Soft Tissue Sar...	Fludarabine Cyclophosphamid... MESNA B7-H3 CAR T cel...	- 21 Years	St. Jude Children's Research Hospital

Spots Global Cancer Trial Database for adrenocortical cancer