MelanomaPhase 2NCT00432107
A Study to Assess APO866 for the Treatment of Advanced Melanoma
A Phase 2 study testing APO866 in people with Melanoma, run by Valerio Therapeutics at 6 sites in 4 countries.
Trial summary
This phase II study is designed to determine the efficacy and safety of APO866 for the treatment of patients with advanced cutaneous melanoma. APO866 has shown to induce growth inhibition in cultures of human melanoma cells as well as in animal models with subcutaneously implanted melanoma tumors. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma
- What is being tested?
- APO866
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 25 participants
- Where
- 6 sitesin 4 countries
- Study dates
- Jul 2006to Mar 2009
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically confirmed diagnosis of melanoma
- Stage IV disease or stage III not amenable to surgery (AJCC, see Appendix A)
- Measurable disease, defined as at least 1 malignant lesion that could be accurately and serially measured in at least 1 dimension and for which the greatest diameter is > or = 10 mm as measured by spiral computed tomography (CT) scan or magnetic resonance imaging (MRI), or > or = 20 mm with conventional techniques. A caliper can be used for the measurement of superficial cutaneous metastases which are > or = 10 mm.
- Patients must be able to undergo either contrast-enhanced CT-scan or contrast-enhanced MRI scan for tumor assessment
- Only one previous systemic treatment (excluding prior systemic treatment as postoperative adjuvant therapy) is allowed and should have been terminated > 4 weeks before Study Day 1 (SD1).
- Lack of response or progression of disease after the most recent systemic therapy for advanced melanoma
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- Patients must have recovered from the toxicity of any previously used treatment. All Adverse events of previous systemic treatment must have resolved to < grade I Common Terminology Criteria for Adverse Events (CTC v3.0, see Appendix)
- Eastern Cooperative Oncology Group (ECOG) Performance Status < 1 (see Appendix C)
- Age > 18 years, of either sex
- Female patients with childbearing potential must be using a hormonal contraceptive, intra uterine device, diaphragm with spermicide or condom with spermicide for the duration of the study. Women of childbearing potential must have a negative serum or urinary human chorionic gonadotropin (hCG) pregnancy test within 7 days prior to Study Day 1 (SD1)
- Male patients, who are not surgically sterile, must use a condom with spermicide for the duration of the study and 3 months thereafter
- Have given written informed consent, prior to any study related procedure not part of the patient's normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
Who cannot join
- Have participated in any other investigational study or received an experimental therapeutic procedure considered to interfere with the study in the 4 weeks preceding SD1
- History of brain metastases or leptomeningeal disease
- Bone-only metastatic disease
- Use of prohibited medication due to Cytochrome P450 3A4 (CYP3A4) metabolism of APO866, as specified in Section 6.6.2. concomitant use of these drugs will not be allowed during the study.
- Use of biphosphonate drug during the 30 days preceding the APO866 infusion and during the treatment period will not be allowed
- Uncontrolled medical conditions, requiring surgical or pharmacological treatment (exceptions must be approved by the Medical Responsible of the study).
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- Serious concomitant disease (e.g. significant cardiac disease)
- History of second cancer that was treated with curative intent and in complete remission for < 5 years, with the exception of basal cell carcinoma or cervical cancer in situ
- Primary or acquired thrombocytopenia
- Inadequate bone marrow reserve: white blood cell (WBC) < 3.5x10^9/L, neutrophils < 1.0x10^9/L, thrombocytes < 100x10^9/L, Hb < 10.0 g/dL or coagulation abnormalities
- Inadequate liver function: total bilirubin > 1.5 x upper limit of normal values (ULN), aspartate aminotransferase (AST), Alanine Amino Transferase (ALT), or alkaline phosphatase > 2.5 x ULN
- Have inadequate renal function, defined by serum creatinine > 1.5x ULN
- Retinopathy, history of retinal laser surgery, or an ERG < 50% of normal
- Pregnant of lactating female
- Abuse of alcohol or other recreational drugs
Trial locations and contacts
6 sites in 4 countries.
6 sites in 4 countries
France2 sites
Department of Dermatology, Hopital Henri Modor
Créteil, 94010
Department of Dermatologie, Hotel Dieu
Nantes, 44093
Germany2 sites
Department of Dermatology, Charité University Hospital Berlin
Berlin, 10117
University Clinic for Dermatology, Medical Faculty of Mannheim of the Heidelberg University
Mannheim, 68167
Switzerland1 site
Department of Dermatology, University Hospital of Zürich
Zurich, 8091
About this study
Official title: A Multi-centre, Two-stage, Open Label Phase II Study to Assess the Efficacy and Safety of APO866 in the Treatment of Patients With Advanced Melanoma.
This phase II study is designed to determine the efficacy and safety of APO866 for the treatment of patients with advanced cutaneous melanoma. APO866 has shown to induce growth inhibition in cultures of human melanoma cells as well as in animal models with subcutaneously implanted melanoma tumors. APO866 was considered to be safe and well tolerated in a phase I study that treated 24 patients with advanced cancer. In that study one of the two patients with advanced melanoma had a stable disease for 5 months with size reduction of some lesions. APO866 is administered by intravenous infusion continuously for 96 hours that is repeated every 4 weeks. Patients will receive 3 cycles of treatment and the primary efficacy endpoint will be assessed at Week 16. Patients will be follow-up for 12 months.
Read the detailed description
Advanced melanoma is one of the most chemo-resistant types of human cancers. The incidence increases by about 2.5% on an annual basis, with may partially be related to aging and growth of the population, as well as other environmental risk factors. Virtually no recent progress has been made in the treatment of patients with this disease. In the past 30 years, the FDA has approved only 2 agents, dacarbazine and interleukin-2, on the basis of overall response and response duration, respectively. However, these outcomes were not accompanied by a survival benefit. The most recent randomized study of Dacarbazine (DTIC) yielded an overall response rate of 7%, and to date, no other treatments, including combination therapies, have shown to improve survival when compared to DTIC alone. Hence, the mainstay of treatment for patients with advanced melanoma is DTIC-based therapy.
APO866 is a novel drug that induces cell death by specifically inhibiting the biosynthesis of Niacinamide Adenine Dinucleotide (NAD+) from niacinamide, which is essential for the cellular metabolism, protein modification and messenger synthesis. APO866 is not subject to the commonly known mechanisms of multi drug resistance (MDR). Its activity is cell cycle independent. APO866 exerted high anti-tumor activity on a broad range of different tumor cells derived from both human solid cancers and leukemias in vitro and on a large number of human xenografts in nude mice, including melanoma, and rats in vivo. Hematologic cancer cells were highly sensitive to APO866. Lymphocytes are the most sensitive normal cells to APO866 resulting in lymphocytopenia and reticulocytopenia in rats, monkeys. Furthermore, APO866 may have anti-angiogenic properties as shown in vivo.
APO866 was investigated in 24 patients with advanced cancers in a phase I study aiming to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). Treatment was well tolerated and safe. The unique DLT was thrombocytopenia. At dose levels higher than 0.036 mg/m2/hr CTC grade III lymphocytopenia, not thought to be clinically relevant, preceded all other toxicities. The recommended dose for phase II studies of APO866 is 0.126 mg/m2/hr administered by civ infusion for 4 consecutive days evry 4 weeks. This dose was selected because of its safety profile, and the translational observation that Css of APO866 at MTD was similar or higher as compared to the concentrations at which efficacy was established in vitro and in vivo. In addition, a transient decrease of serum vascular endothelial growth factor (VEGF) levels, a surrogate marker of angiogenesis, was observed within 96 hrs after the start of treatment in 9 out of 11 patients treated at MTD and the 0.144 mg/m2/hr dose level of APO866.
No objective tumor response was observed. However, 4 patients had stable disease for at least 3 months: prostate cancer (4 months), melanoma (5 months), sarcomatoid mesothelioma (3 months) and oropharyngeal cancer (5 months). In addition, lesion size reductions were observed in the melanoma patient (80% size reduction and stable size of other lesions) at an APO866 dose level of 0.072 mg/m2/hr, and in the mesothelioma patient (moderate size reductions of pleural lesions) at 0.108 mg/m2/hr.
Treatment with APO866 was safe and well tolerated. The anti-tumor effect of APO866, in particular on melanoma cells in vitro and in vivo, and its anti-angiogenic propriety support the rationale to conduct a open phase II study of APO866 in patients with advanced melanoma.
- Conditions
- Melanoma
- Being tested
- APO866
- Keywords
- Advanced cutaneous melanoma, Phase II study
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
APO866Drug
APO866 is administered as 0.126 mg/m²/hr IV every 4 weeks for 4 consecutive days (96 hours) for a total of 3 cycles
| Study group | Role | What they receive |
|---|---|---|
| 2-stage mono therapy of APO866 | Experimental | The treatment period consists of 3 consecutive 28 day cycles. Each cycle starts with a 4 day continuous infusion of the study medication followed by a 24 day break Receives: Drug: APO866 |
What is being measured
The primary outcome is the main question the study is designed to answer.
To determine the tumor response rate (according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria) as the proportion of eligible patients with stage IV cutaneous melanoma or stage III not amenable to surgery.
Measured: Week 16
Secondary outcomes (6)
Safety and tolerability
Measured: Week 16 and 12 months follow-up
Time to response
Measured: Week 16
Duration of response
Measured: Week 16
Progression free survival
Measured: 12 months
Overall survival
Measured: 12 months
Evolution of serum VEGF and interleukin-8 (IL-8) during treatment
Measured: Week 16
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Feb 2007 (estimated)
- Study startJul 2006
- Primary completionFeb 2008
- Study completionMar 2009
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for MelanomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 25 participants (actual)
Sponsor and investigators
- Lead sponsor
- Valerio Therapeutics
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Uwe Trefzer, MD PhD, Principal investigator, Department of Dermatology, Charité University Hospital, Schumannstrasse 20-21, 10117 Berlin, Germany
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00432107
- Sponsor's protocol ID
- AP3003
- Status last verified
- Nov 2013
- First submitted
- 6 Feb 2007
- Last updated
- 29 Sep 2015
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 29 Sep 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multi-centre, Two-stage, Open Label Phase II Study to Assess the Efficacy and Safety of APO866 in the Treatment of Patients With Advanced Melanoma.
- ClinicalTrials.gov ID
- NCT00432107
- Acronym / sponsor ID
- AP3003
- Conditions
- Melanoma
- Keywords
- Advanced cutaneous melanoma, Phase II study
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 25 participants (actual)
- Lead sponsor
- Valerio TherapeuticsIndustry (pharma, biotech, devices)
- Study start
- Jul 2006
- Primary completion
- Feb 2008 (actual)
- Study completion
- Mar 2009 (actual)
- First posted
- 7 Feb 2007 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This phase II study is designed to determine the efficacy and safety of APO866 for the treatment of patients with advanced cutaneous melanoma. APO866 has shown to induce growth inhibition in cultures of human melanoma cells as well as in animal models with subcutaneously implanted melanoma tumors. APO866 was considered to be safe and well tolerated in a phase I study that treated 24 patients with advanced cancer. In that study one of the two patients with advanced melanoma had a stable disease for 5 months with size reduction of some lesions. APO866 is administered by intravenous infusion continuously for 96 hours that is repeated every 4 weeks. Patients will receive 3 cycles of treatment and the primary efficacy endpoint will be assessed at Week 16. Patients will be follow-up for 12 months.
Detailed description
Advanced melanoma is one of the most chemo-resistant types of human cancers. The incidence increases by about 2.5% on an annual basis, with may partially be related to aging and growth of the population, as well as other environmental risk factors. Virtually no recent progress has been made in the treatment of patients with this disease. In the past 30 years, the FDA has approved only 2 agents, dacarbazine and interleukin-2, on the basis of overall response and response duration, respectively. However, these outcomes were not accompanied by a survival benefit. The most recent randomized study of Dacarbazine (DTIC) yielded an overall response rate of 7%, and to date, no other treatments, including combination therapies, have shown to improve survival when compared to DTIC alone. Hence, the mainstay of treatment for patients with advanced melanoma is DTIC-based therapy.
APO866 is a novel drug that induces cell death by specifically inhibiting the biosynthesis of Niacinamide Adenine Dinucleotide (NAD+) from niacinamide, which is essential for the cellular metabolism, protein modification and messenger synthesis. APO866 is not subject to the commonly known mechanisms of multi drug resistance (MDR). Its activity is cell cycle independent. APO866 exerted high anti-tumor activity on a broad range of different tumor cells derived from both human solid cancers and leukemias in vitro and on a large number of human xenografts in nude mice, including melanoma, and rats in vivo. Hematologic cancer cells were highly sensitive to APO866. Lymphocytes are the most sensitive normal cells to APO866 resulting in lymphocytopenia and reticulocytopenia in rats, monkeys. Furthermore, APO866 may have anti-angiogenic properties as shown in vivo.
APO866 was investigated in 24 patients with advanced cancers in a phase I study aiming to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). Treatment was well tolerated and safe. The unique DLT was thrombocytopenia. At dose levels higher than 0.036 mg/m2/hr CTC grade III lymphocytopenia, not thought to be clinically relevant, preceded all other toxicities. The recommended dose for phase II studies of APO866 is 0.126 mg/m2/hr administered by civ infusion for 4 consecutive days evry 4 weeks. This dose was selected because of its safety profile, and the translational observation that Css of APO866 at MTD was similar or higher as compared to the concentrations at which efficacy was established in vitro and in vivo. In addition, a transient decrease of serum vascular endothelial growth factor (VEGF) levels, a surrogate marker of angiogenesis, was observed within 96 hrs after the start of treatment in 9 out of 11 patients treated at MTD and the 0.144 mg/m2/hr dose level of APO866.
No objective tumor response was observed. However, 4 patients had stable disease for at least 3 months: prostate cancer (4 months), melanoma (5 months), sarcomatoid mesothelioma (3 months) and oropharyngeal cancer (5 months). In addition, lesion size reductions were observed in the melanoma patient (80% size reduction and stable size of other lesions) at an APO866 dose level of 0.072 mg/m2/hr, and in the mesothelioma patient (moderate size reductions of pleural lesions) at 0.108 mg/m2/hr.
Treatment with APO866 was safe and well tolerated. The anti-tumor effect of APO866, in particular on melanoma cells in vitro and in vivo, and its anti-angiogenic propriety support the rationale to conduct a open phase II study of APO866 in patients with advanced melanoma.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 2-stage mono therapy of APO866 | Experimental | Drug: APO866The treatment period consists of 3 consecutive 28 day cycles. Each cycle starts with a 4 day continuous infusion of the study medication followed by a 24 day break |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Histologically confirmed diagnosis of melanoma
- Stage IV disease or stage III not amenable to surgery (AJCC, see Appendix A)
- Measurable disease, defined as at least 1 malignant lesion that could be accurately and serially measured in at least 1 dimension and for which the greatest diameter is > or = 10 mm as measured by spiral computed tomography (CT) scan or magnetic resonance imaging (MRI), or > or = 20 mm with conventional techniques. A caliper can be used for the measurement of superficial cutaneous metastases which are > or = 10 mm.
- Patients must be able to undergo either contrast-enhanced CT-scan or contrast-enhanced MRI scan for tumor assessment
- Only one previous systemic treatment (excluding prior systemic treatment as postoperative adjuvant therapy) is allowed and should have been terminated > 4 weeks before Study Day 1 (SD1).
Key exclusion criteria (15 listed)
- Have participated in any other investigational study or received an experimental therapeutic procedure considered to interfere with the study in the 4 weeks preceding SD1
- History of brain metastases or leptomeningeal disease
- Bone-only metastatic disease
- Use of prohibited medication due to Cytochrome P450 3A4 (CYP3A4) metabolism of APO866, as specified in Section 6.6.2. concomitant use of these drugs will not be allowed during the study.
- Use of biphosphonate drug during the 30 days preceding the APO866 infusion and during the treatment period will not be allowed
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| APO866APO866 is administered as 0.126 mg/m²/hr IV every 4 weeks for 4 consecutive days (96 hours) for a total of 3 cycles | Drug | 2-stage mono therapy of APO866 |
Primary outcome
To determine the tumor response rate (according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria) as the proportion of eligible patients with stage IV cutaneous melanoma or stage III not amenable to surgery.
Time frame: Week 16
6 secondary outcomes
Safety and tolerability
Time frame: Week 16 and 12 months follow-up
Time to response
Time frame: Week 16
Duration of response
Time frame: Week 16
Progression free survival
Time frame: 12 months
Overall survival
Time frame: 12 months
Evolution of serum VEGF and interleukin-8 (IL-8) during treatment
Time frame: Week 16
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Sep 2015.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Uwe Trefzer, MD PhD principal investigator
Department of Dermatology, Charité University Hospital, Schumannstrasse 20-21, 10117 Berlin, Germany
6 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing APO866 in people with Melanoma, run by Valerio Therapeutics at 6 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Sep 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in France, Germany, Austria, Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
To determine the tumor response rate (according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria) as the proportion of eligible patients with stage IV cutaneous melanoma or stage III not amenable to surgery. (time frame: Week 16). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Sep 2015.