Cabazitaxel Activity in Patients With Advanced AdrenoCortical-Carcinoma Progressing After Previous Chemotherapy Lines

Adrenocortical Carcinoma Clinical Trial

— CabACC  

Official title:

Multicenter, Prospective, Non-randomized, Phase II Trial Designed to Evaluate the Activity of Cabazitaxel in Patients With Advanced Adreno-Cortical- Carcinoma Progressing After Previous Chemotherapy Lines

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03257891
• Other study ID #: NP2729
• Status: Recruiting
• Phase: Phase 2
• First received: August 17, 2017
• Last updated: April 10, 2018
• Start date: January 25, 2018
• Est. completion date: January 24, 2022

Study information

• Verified date: April 2018
• Source: Azienda Ospedaliera Spedali Civili di Brescia
• Contact: Alfredo Berruti, MD
• Phone: 030399
• Email: alfredo.berruti[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Adrenocortical cancer (ACC) is a rare aggressive tumor. The treatment of metastatic ACC is challenging and the current available treatments are mitotane, chemotherapy or the combination of both. Prognosis in locally advanced inoperable and metastatic ACC patients still remains poor, the 5-year overall survival being <15%. New treatment strategies are therefore needed. The taxanes are a class of drugs targeting the microtubules that have shown to be effective in the treatment of several malignancies but have not been fully developed in patients with ACC. Cabazitaxel is a new taxoid which promotes the tubulin assembly in vitro and stabilizes microtubules against cold-induced depolymerization as efficiently as docetaxel. Cabazitaxel was selected for development based on a better antiproliferative activity on resistant cell lines than docetaxel. The activity of the drug against several malignancies is currently tested in ongoing prospective studies, but to our knowledge neither preclinical nor clinical studies are currently testing cabaztaxel in ACC. This study is aimed to demonstrate that cabazitaxel is active in ACC, but the drug was never tested before in this clinical setting. A prospective, non-randomized, multicentre, open label, single arm, phase II study will be conducted in patients with advanced ACC. The phase II study will be conducted in 2 different Italian Institutions that are reference centers for ACC.

Description:

CABAZITAXEL ADMINISTRATION Cabazitaxel will be administered at dose of 25 mg/m2 every 3 weeks, administered by IV route in 1 hour, for a maximum of 6 total cycles. The drug will be provided by Sanofi -Aventis S.p.A. Concomitant mitotane therapy will not be permitted however mitotane will be maintained in patients with hormone secreting tumors. Cycle length for cabazitaxel is 3 weeks. New cycles of therapy may not begin until Absolute Neutrophil Count (ANC) ≥1500/mm3, platelet count ≥75 000/mm3, and non-hematological toxicities (except alopecia) have recovered to baseline.

A maximum of 2 weeks delay is allowed between 2 treatment cycles.

PHARMACOKINETIC STUDY Another study aims will be to assess the toxicity of cabazitaxel therapy in ACC patients. As mitotane notoriously interfere with the metabolism of several drugs (11), an ancillary study will be conducted to assess the pharmacokinetic profile of cabazitaxel in the patient population with hormone secreting tumors that will maintain mitotane administration vs patients with non secreting ACC in which mitotane will be stopped. Blood samples will be collected in lithium heparinized tubes at fixed time points before and after drug infusion: Cycles 1 on Day 1 just before infusion, 30 min after start of infusion, 5 min before the end of 1-hour infusion (Tmax), 24 h, 48h and 96 h post-infusion. Cabazitaxel serum concentrations will be measured in plasma using a validated liquid chromatography-tandem mass spectrometry method: the Agilent 1260 Infinity LC equipped with an Agilent 6460 Triple Quadrupole Mass Spectrometer (QQQ) in electrospray mode systems.

STATISTICAL ANALYSIS All data collected at baseline, including recorded and derived variables will be described on all patients by means of summary descriptive statistics: mean, standard deviation, median, min, max, 25th and 75th percentiles for continuous variables; absolute and relative frequency for categorical variables. The relative frequencies will be calculated on the total patients with and without missing data. Whenever possible the data will be described by visit.

Chi square ore Fisher test, when applicable will be employed to compare categorical variables. Student T-test and analysis of variance for parametric or Wilcoxon's matched pairs signed-rank test and Friedman analysis of variance for non parametric data will be used to compare paired data. Simple correlation analysis will be performed by Spearman rho (coefficient of Spearman's rank correlation) for nonparametric distribution. Two-tailed tests will be used for all comparisons and p <0.05. All survival functions will computed using the Kaplan-Meier method. Survival curves will be compared with the log rank test.

CONCOMITANT MEDICATION Concurrent treatment with strong inhibitors and strong inducers of cytochrome P450 3A4 is not permitted. For patients who were receiving treatment with such agents, a 2-week washout period is required prior to randomization. Concurrent participation in another clinical trial or treatment with any other anti-cancer therapy is also not permitted. The Investigator may prescribe any other concomitant medications as deemed necessary.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 25
• Est. completion date: January 24, 2022
• Est. primary completion date: January 24, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically confirmed diagnosis of ACC

• Locally advanced or metastatic disease not amenable to radical surgery resection

• Radiologically monitorised disease

• Progressing disease after one to three cytotoxic chemotherapy regimes (including a platin-based protocol)

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Life expectancy = 3 months

• Age = 18 years

• Adequate bone marrow reserve (neutrophils = 1500/mm³ and platelets > 100.000/mm³)

• Effective contraception in pre-menopausal female and male patients

• Patient´s written informed consent

• Ability to comply with the protocol procedures

• Mitotane intake should be stopped one months before the study entry

Exclusion Criteria:

• History of prior malignancy, except for cured non-melanoma skin cancer, cured in situ cervical carcinoma, or other treated malignancies with no evidence of disease for at least three years.

• Serum creatinine > 1.5 x ULN or hepatic insufficiency, Hemoglobin <10.0 g/dL;

• Total bilirubin >1x ULN, Creatinine < 1.5 ULN;

• Decompensated heart failure (ejection fraction <45%), myocardial infarction or revascularization procedure during the last 6 months, unstable angina pectoris, uncontrolled cardiac arrhythmia

• Pregnancy or breast feeding

• Any other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study

• Patients with serum levels of mitotane (evaluated one week before the study start) in the therapeutic range (14-20 mcg/ml).History of severe hypersensitivity reaction (=grade 3) to docetaxel

• History of severe hypersensitivity reaction (=grade 3) to polysorbate 80 containing drugs

• Uncontrolled severe illness or medical condition (including uncontrolled diabetes mellitus)

• Concurrent or planned treatment with strong inhibitors or strong inducers of cytochrome P450 3A4/5 (a one week wash-out period is necessary for patients who are already on these treatments) (see Annex 1 and Annex 2)

• Concomitant vaccination with yellow fever vaccine

Related Conditions & MeSH terms

• Adrenocortical Carcinoma
• Carcinoma

Intervention

Drug:
• Cabazitaxel
Cabazitaxel will be administered every 21 days

Locations

Country	Name	City	State
Italy	Azienda Ospedaliera Spedali Civili di Brescia	Brescia

Sponsors (2)

Lead Sponsor	Collaborator
Azienda Ospedaliera Spedali Civili di Brescia	San Luigi Gonzaga Hospital

Country where clinical trial is conducted

Italy, 

References & Publications (14)

Arrighi N, Bodei S, Lucente A, Michel MC, Zani D, Simeone C, Cunico SC, Spano P, Sigala S. Muscarinic receptors stimulate cell proliferation in the human urothelium-derived cell line UROtsa. Pharmacol Res. 2011 Oct;64(4):420-5. doi: 10.1016/j.phrs.2011.06 — View Citation

Bates SE, Shieh CY, Mickley LA, Dichek HL, Gazdar A, Loriaux DL, Fojo AT. Mitotane enhances cytotoxicity of chemotherapy in cell lines expressing a multidrug resistance gene (mdr-1/P-glycoprotein) which is also expressed by adrenocortical carcinomas. J Cl — View Citation

Berruti A, Ferrero A, Sperone P, Daffara F, Reimondo G, Papotti M, Dogliotti L, Angeli A, Terzolo M. Emerging drugs for adrenocortical carcinoma. Expert Opin Emerg Drugs. 2008 Sep;13(3):497-509. doi: 10.1517/14728214.13.3.497 . Review. — View Citation

Berruti A, Sperone P, Ferrero A, Germano A, Ardito A, Priola AM, De Francia S, Volante M, Daffara F, Generali D, Leboulleux S, Perotti P, Baudin E, Papotti M, Terzolo M. Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in pat — View Citation

Berruti A, Terzolo M, Sperone P, Pia A, Della Casa S, Gross DJ, Carnaghi C, Casali P, Porpiglia F, Mantero F, Reimondo G, Angeli A, Dogliotti L. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a la — View Citation

Chen KG, Sikic BI. Molecular pathways: regulation and therapeutic implications of multidrug resistance. Clin Cancer Res. 2012 Apr 1;18(7):1863-9. doi: 10.1158/1078-0432.CCR-11-1590. Epub 2012 Feb 16. Review. — View Citation

Demeure MJ, Stephan E, Sinari S, Mount D, Gately S, Gonzales P, Hostetter G, Komorowski R, Kiefer J, Grant CS, Han H, Von Hoff DD, Bussey KJ. Preclinical investigation of nanoparticle albumin-bound paclitaxel as a potential treatment for adrenocortical ca — View Citation

Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S, Schade-Brittinger C, Lacroix A, Jarzab B, Sorbye H, Torpy DJ, Stepan V, Schteingart DE, Arlt W, Kroiss M, Leboulleux S, Sperone P, Sundin A, Hermsen I, Hahner S, Willenberg HS, Tabar — View Citation

Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 No — View Citation

Hasegawa E, Nakagawa S, Sato M, Tachikawa E, Yamato S. Effect of polyphenols on production of steroid hormones from human adrenocortical NCI-H295R cells. Biol Pharm Bull. 2013;36(2):228-37. — View Citation

Kroiss M, Quinkler M, Lutz WK, Allolio B, Fassnacht M. Drug interactions with mitotane by induction of CYP3A4 metabolism in the clinical management of adrenocortical carcinoma. Clin Endocrinol (Oxf). 2011 Nov;75(5):585-91. doi: 10.1111/j.1365-2265.2011.04 — View Citation

Mita AC, Figlin R, Mita MM. Cabazitaxel: more than a new taxane for metastatic castrate-resistant prostate cancer? Clin Cancer Res. 2012 Dec 15;18(24):6574-9. doi: 10.1158/1078-0432.CCR-12-1584. Epub 2012 Oct 22. — View Citation

Montoya M, Brown JW, Fishman LM. Comparative effects of chemotherapeutic agents on the growth and survival of human adrenal carcinoma cells in culture. Horm Metab Res. 2008 May;40(5):302-5. doi: 10.1055/s-2008-1073139. — View Citation

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* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To assess the clinical benefit after 4 months of the cabazitaxel in patients with locally advanced or metastatic ACC who progressed after cytotoxic therapy.	CT scan evaluated according to RECIST 1.1 criteria	4 months
Secondary	Assessment of Objective Response Rates (ORR)	ORR evaluated by RECIST criteria	Every cycle (21 days) for a maximum of 6 cycles and for 6 months follow up. Total 1 year
Secondary	Assessment of overall survival	defined as the time from the date of the study start to date of death due to any cause	Every cycle (21 days) for a maximum of 6 cycles and for 6 months follow up. Total 1 year
Secondary	Assessment of quality of life	EORTC quality of life questionnaire (QLQ)-C30 will be administered to patients	Every cycle (21 days) for a maximum of 6 cycles and for 6 months follow up. Total 1 year
Secondary	Assessment of toxicity	evaluated by NCI CTCAE V4.03 criteria	Every cycle (21 days) for a maximum of 6 cycles and for 6 months follow up. Total 1 year
Secondary	Assessment of hormone response	Evaluation of adrenocorticotropic hormone (ACTH), Testosterone, Progesterone, Cortisol, (Deidroepiandrosterone) DHEA-S, 17-hydroxide- progesterone, Androstenedione in serum. Evaluation of 24 hours urinary cortisol.	Every cycle (21 days) for a maximum of 6 cycles and for 6 months follow up. Total 1 year