Study of Artesunate in Metastatic Breast Cancer (ARTIC-M33/2)

• ClinicalTrials.gov Identifier: NCT00764036
• Recruitment Status: Completed
• First Posted: October 1, 2008
• Last Update Posted: August 1, 2017
• Sponsor: Heidelberg University
• Collaborators: Hector-Stiftung; Dafra Pharma; Monika-Kutzner Stiftung, Berlin, Germany; HEIFAN-Heidelberger Förderverein d. Ambulanz f. Naturheilkunde eV, Heidelberg, Germany
• Information provided by (Responsible Party): Cornelia von Hagens, Heidelberg University

Study Description

Brief Summary:

The purpose of this study is to evaluation the tolerability of an add-on therapy with artesunate with a duration of 4 weeks in patients with advanced breast cancer.

Condition or disease	Intervention/treatment	Phase
Metastatic Breast Cancer; Locally Advanced Breast Cancer	Drug: artesunate	Phase 1

Detailed Description:

Additional objectives are:

• parallel sampling of blood and saliva for the determination of drug concentrations and pharmacokinetic parameters in a substudy on the day of first application and during steady state
• attempt to establish a therapeutical drug monitoring
• collection of further safety data during prolonged add-on treatments (compassionate use)

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 23 participants
• Intervention Model: Sequential Assignment
• Intervention Model Description: dose escalation
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Prospective Open Uncontrolled Phase I Study of Compatibility, Safety&Pharmacokinetics of Artesunate, a Semisynthetic Derivative of Artemisinin From the Chinese Herb Artemisia Annua in Patients With Metastatic/Locally Advanced Breast Cancer
• Actual Study Start Date: October 2008
• Actual Primary Completion Date: November 2013
• Actual Study Completion Date: November 2013

Arms and Interventions

Arm	Intervention/treatment
Experimental: experimental arm only; add-on therapy with 100, 150 or 200 mg oral artesunate once daily	Drug: artesunate; add-on therapy with daily single oral doses of 100, 150 or 200 mg of artesunate; Other Names: artesunic acid hemisuccinate; dihydroqinghaosu hemisuccinate

Outcome Measures

Primary Outcome Measures :

1. Dose limiting adverse events with possible, probable or definite relation with the respective dose level of the add-on therapy [ Time Frame: 8-12 weeks ]

Secondary Outcome Measures :

1. Adverse events relation between adverse events and add-on therapy, cortisol profile in saliva, overall response rate, clinical benefit, assessment of patients expectations [ Time Frame: 8-12 weeks ]

Other Outcome Measures:

1. Further safety data (adverse events) during prolonged treatments latest till the second progression during the add-on therapy with the study medication (compassionate use) [ Time Frame: add-on treatments > 4+/- 1 weeks ]
2. Collection of further safety data during later individual compassionate use with monitoring if approbriate for the patients' health status [ Time Frame: Depending on patients' preference and health status ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Patients with histologically or cytologically confirmed breast cancer
• Distant metastases or locally advanced breast cancer
• Age ≥ 18 years
• ECOG performance ≤ 2
• Life expectancy of at least 6 months
• Written informed consent
• individual standard therapy according to guidelines
• Oral intake of trial medication possible
• Compliance with study procedures
• Women of childbearing potential: negative pregnancy test before start of medication
• Use of a highly effective method of birth control during intake of add-on therapy for women of childbearing potential being sexually active

Inclusion Criteria for Extended Treatment Phase:

• Participant of the phase I study ARTIC M33/2 who had tolerated the study medication for 4±1 weeks without clinically relvant adverse events or after improvement to ≤ grade 2
• Participant of the phase I study ARTIC M33/2 with possible benefit by continuation or restart of the add-on therapy after a next progression according to current scientific knowledge
• Written informed consent for extended treatment phase
• Consent of the responsible oncologist
• Compliance for further intake and follow-up expected

Inclusion Criteria for Individual Compassionate Use:

• Participant of the phase I study ARTIC M33/2
• Available standard therapies have minimal or only short activity or intolerable side effects
• Written informed consent for compassionate use
• Consent of the responsible oncologist

Exclusion Criteria:

• Allergy to artesunate or to other artemisinin derivatives
• Concurrent conditions interfering with patient safety
• Communication problems
• Concurrent participation in another clinical trial or 4 weeks prior to recruitment
• Participation in a clinical trial with an unapproved drug 6 months prior to recruitment
• Sinus bradycardia, bradyarrhythmia
• AV-Block II° and III°
• QTc > 500 msec
• Previously known long QT-syndrome
• Concurrent intake of a medication with clinically relevant neurotoxicity or during 30 days prior to recruitment
• Relevant neurological symptoms which might complicate the evaluation of the compatibility of the IMPD (f. e. cerebral metastases) or might be subject to worsening during intake of the IMPD
• Radiotherapy 2 weeks prior of the intake of the IMPD
• Concurrent intake of supplements or any other medication with unapproved efficacy f.e. vitamins, minerals or others (OTC)
• Pregnancy and lactation
• Ineffective mode of contraception in women of childbearing potential

Exclusion Criteria for Extended Treatment Phase:

• Clinically relevant adverse Events during the first 4 weeks of intake of study medication possibly, probably or definitely related to the study medication
• Intolerable health risks by continuation re-exposition with the study medication
• Continuation or re-exposition is medically not acceptable after consultation of physicians responsible for their standard therapy

Exclusion Criteria for Individual Compassionate Use:

- Intolerable health risks by re-exposition with the study medication

Contacts and Locations

Locations

Germany

Complementary and Integrative Medicine, Dep. Gyn. Endocrinology, Women's Hospital, University of Heidelberg

Heidelberg, Baden-Württemberg, Germany, D-69120

Sponsors and Collaborators

Heidelberg University

Hector-Stiftung

Dafra Pharma

Monika-Kutzner Stiftung, Berlin, Germany

HEIFAN-Heidelberger Förderverein d. Ambulanz f. Naturheilkunde eV, Heidelberg, Germany

Investigators

• Principal Investigator: Cornelia U v. Hagens, MD; Department of Gynecological Endocrinology and Reproductive Medicine

More Information

Publications of Results:

von Hagens C, Walter-Sack I, Goeckenjan M, Osburg J, Storch-Hagenlocher B, Sertel S, Elsasser M, Remppis BA, Edler L, Munzinger J, Efferth T, Schneeweiss A, Strowitzki T. Prospective open uncontrolled phase I study to define a well-tolerated dose of oral artesunate as add-on therapy in patients with metastatic breast cancer (ARTIC M33/2). Breast Cancer Res Treat. 2017 Jul;164(2):359-369. doi: 10.1007/s10549-017-4261-1. Epub 2017 Apr 24.

Konig M, von Hagens C, Hoth S, Baumann I, Walter-Sack I, Edler L, Sertel S. Investigation of ototoxicity of artesunate as add-on therapy in patients with metastatic or locally advanced breast cancer: new audiological results from a prospective, open, uncontrolled, monocentric phase I study. Cancer Chemother Pharmacol. 2016 Feb;77(2):413-27. doi: 10.1007/s00280-016-2960-7. Epub 2016 Jan 21. Erratum In: Cancer Chemother Pharmacol. 2016 Jun;77(6):1321.

Konig M, von Hagens C, Hoth S, Baumann I, Walter-Sack I, Edler L, Sertel S. Erratum to: Investigation of ototoxicity of artesunate as add-on therapy in patients with metastatic or locally advanced breast cancer: new audiological results from a prospective, open, uncontrolled, monocentric phase I study. Cancer Chemother Pharmacol. 2016 Jun;77(6):1321. doi: 10.1007/s00280-016-3023-9. No abstract available.

Ericsson T, Blank A, von Hagens C, Ashton M, Abelo A. Population pharmacokinetics of artesunate and dihydroartemisinin during long-term oral administration of artesunate to patients with metastatic breast cancer. Eur J Clin Pharmacol. 2014 Dec;70(12):1453-63. doi: 10.1007/s00228-014-1754-2. Epub 2014 Sep 25.

Other Publications:

Birgersson S, Ericsson T, Blank A, Hagens Cv, Ashton M, Hoffmann KJ. A high-throughput LC-MS/MS assay for quantification of artesunate and its metabolite dihydroartemisinin in human plasma and saliva. Bioanalysis. 2014 Sep;6(18):2357-69. doi: 10.4155/bio.14.116.

• Responsible Party: Cornelia von Hagens, Head Complementary & Integrative Medicine, Dep. 4.2, Heidelberg University
• ClinicalTrials.gov Identifier: NCT00764036
• Other Study ID Numbers: M33/2
• First Posted: October 1, 2008
• Last Update Posted: August 1, 2017
• Last Verified: July 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Cornelia von Hagens, Heidelberg University:

phase I; safety

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Artesunate; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Anti-Infective Agents; Antineoplastic Agents; Antiviral Agents; Schistosomicides; Antiplatyhelmintic Agents; Anthelmintics