E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027481 |
E.1.2 | Term | Metastatic melanoma |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of study is to assess if the addition of ABT-888 to temozolomide (TMZ) can prolong Progression Free Survival (PFS) compared to TMZ alone in subjects with metastatic melanoma (MM). |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study will be to determine overall survival, 12 month overall survival rate, 6 month progression free survival rate, objective response rate, disease control rate, time to disease progression, duration of overall response, quality of life, safety and tolerability, time to neurological/brain progression. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Subjects will have the option to participate in the following substudies:
a) Tissue sample collection: Subjects may consent to providing archived tissue samples taken from a biopsy that was performed at the time of their melanoma diagnosis. These tissue samples may help researchers develop a diagnostic test to identify patients most likely to respond to the drug.
b) Genetic sub-study: Subjects may consent to an additional blood draw that will be used for genetic testing to help determine why some metastatic melanoma patients may benefit from taking ABT-888 more than others do.
c) Needle biopsy tissue collection: Subjects may consent to having percutaneous tumor biopsies performed. These biopsies will help to identify biomarkers that may predict how a patient will respond to ABT-888.
A subject may participate in the main portion of the M10-440 study without agreeing to participate in any, or all of the optional substudies. |
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E.3 | Principal inclusion criteria |
1. Subject must be at least 18 years of age.
2. Histologically (or cytologically) confirmed metastatic melanoma.
3. Unresectable Stage III or Stage IV metastatic melanoma.
4. Subject has measurable disease, defined as at least 1 unidimensionally measurable lesion on a CT scan as defined by RECIST.
5. Subjects with no brain metastases or a history of previously treated brain metastatases who:
• Have been treated by surgery or stereotactic radiosurgery (SRS) at least 4 weeks prior to enrollment; and
• Have a baseline MRI that shows no evidence of active intercranial disease;
and
• Have not had treatment with steroids within 1 week of study enrollment are eligible.
6. At least 28 days since prior anti-cancer therapy.
7. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-1.
8. Subjects must have adequate hematologic, renal and hepatic function as follows:
• Bone Marrow: Absolute neutrophil count (ANC) > 1,500/mm3 (1.5 x 109/L); Platelets > 100,000/mm3 (100 x 109/L); Hemoglobin > 10.0g/dL (1.4 mmol/L)
• Renal function: Serum creatinine < 1.5 x upper normal limit of institution’s normal range OR creatinine clearance > 50 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal
• Hepatic function:
o AST and/ or ALT < 2.5 x the upper normal limit of institution’s normal range. For subjects with liver metastases, AST and /or ALT < 5 x the upper normal limit of institution’s normal range:
o LDH < 2.0 x the upper normal limit of institution’s normal range;
o Bilirubin < 1.5 x the upper normal limit of institution’s normal range. Subjects with Gilbert’s Syndrome may have a bilirubin > 1.5 x the upper normal limit of institution’s normal range.
• Sodium levels must be between 130 mmol/L and 150 mmol/L
• Calcium levels must be between 8.00 mg/dL and 11.5 mg/dL.
9. PTT must be less than or equal to 1.5 x upper normal limit of institution's normal range and INR < 1.5. Subjects on anticoagulant (such as coumadin) will have PTT and INR as determined by the investigator.
10. Subject's with significant fluid retention, including ascites or pleural effusion, may be allowed at the discretion of the PI.
11. Life expectancy > 12 weeks.
12. Women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation and for 90 days following completion of therapy. Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to initiation of treatment and/or post menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential.
13. Subject is capable of understanding and complying with parameters as outlined in the protocol and able to sign and date the informed consent, approved by an IEC/IRB, prior to the initiation of any screening or study-specific procedures.
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E.4 | Principal exclusion criteria |
1. LDH > 2 x the upper normal limit of institutition's normal range.
2. Subjects with ocular malignant melanoma (all other melanoma subtypes are allowed).
3. A subject with a history of CNS metastases or leptomeningeal disease who does not meet the criteria outlined in inclusion criteria 5 is not eligible to participate.
4. Prior therapy with regimens containing DTIC or TMZ are excluded.
5. The subject has received prior DNA damaging agents or cytotoxic chemotherapy (prior therapies with biologic agents including IL-2, interferon, vaccines, immunostimulants and signal transduction inhibitors are allowed).
6. Prior treatment with Whole Brain Radiation Therapy (WBRT).
7. The subject has received an investigational agent within 28 days prior to study drug administration.
8. Subjects with a history of seizure disorder and/or subjects currently receiving medications for seizure disorders (e.g., steroid or EIACD's).
9. The subject has had another active malignancy within the past five years except for cervical cancer in situ, in situ carcinoma of the bladder or non-melanoma
carcinoma of the skin.
10. Clinically significant and uncontrolled major medical condition(s) including but not limited to:
● active uncontrolled infection,
● symptomatic congestive heart failure,
● unstable angina pectoris or cardiac arrhythmia,
● psychiatric illness/social situation that would limit compliance with study requirements.
11. Any medical condition, which in the opinion of the study investigator places the subject at an unacceptably high risk for toxicities.
12. Lactating or pregnant female. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression Free Survival |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end-of-study is defined as the date of the last subject's last scheduled visit. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |