| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with previously untreated carcinoma of unknown primary |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with previously untreated cancer where the origin of the cancer is unknown |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10007460 |
| E.1.2 | Term | Carcinoma of unknown primary |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To provide an estimate of the hazard ratio of treatment effect when the combination of belinostat plus carboplatin and paclitaxel (BelCaP) is compared with the combination of carboplatin and paclitaxel in terms of progression-free survival for patients with carcinoma of unknown primary site.
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| E.2.2 | Secondary objectives of the trial |
•To evaluate and compare further efficacy parameters (overall survival, objective response rate according to RECIST criteria, time to response, duration of response, and time to progression) in the randomized treatment groups receiving belinostat plus carboplatin and paclitaxel (BelCaP) or the combination of carboplatin and paclitaxel.
•To evaluate and compare the safety profiles of the same randomized treatment groups using the NCI-CTC (version 3.0).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Patients with carcinoma of unknown primary where the primary site had not been revealed by complete history, physical examination (including gynecological examination when appropriate), computed tomography scan of the chest, abdomen and pelvis, bilateral mammography (in women with adenocarcinoma or poorly differentiated carcinoma), routine laboratory studies (complete blood cell counts, electrolytes, urinalysis, liver and renal function tests), and directed work-up of any other symptomatic areas.
2.Light microscopic pathologic diagnosis of adenocarcinoma (including poorly differentiated), squamous cell carcinoma, or poorly differentiated carcinoma. Patients with poorly differentiated carcinoma must have immunohistochemical stains to confirm the diagnosis of carcinoma, and to rule out other tumor types. Note, patients with a light microscopic histology diagnosis of "poorly differentiated neoplasm, not otherwise classified" do not fulfill the criteria for inclusion, unless immunohistochemical staining confirms the diagnosis of carcinoma.
3.Signed consent of an IRB/Ethics committee approved informed consent form.
4.At least one measurable lesion according to RECIST criteria. Note, target lesions can only be selected within previously irradiated areas if newly arising or clearly progressing after irradiation as proven by repeat scanning.
5.Performance status (ECOG) ≤ 2.
6.Age ≥18 years.
7.A negative serum or urine pregnancy test for women of childbearing potential. Postmenopausal women must have been amenorrheic for ≥ 12 months to be considered of non-childbearing potential.
8.Serum potassium within normal range.
9.Acceptable coagulation status: PT or INR, and APTT ≤ 1.5 x upper limit of normal (ULN) or in the therapeutic range if on anticoagulation therapy.
10.Acceptable liver, renal and bone marrow function including the following:
• Bilirubin ≤ 1.5 times ULN (if liver metastases are present, then ≤ 3 x ULN is allowed)
• AST (SGOT), and ALT (SGPT), and Alkaline Phosphatase ≤ 3 times ULN (if liver metastases are present, then ≤ 5 x ULN is allowed)
• An estimated creatinine clearance ≥ 45 mL/min using an appropriate formula (see Section 13.3), or measured EDTA renal clearance ≥ 45 mL/min
• Absolute neutrophils count ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L
• Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L (patients with chronic anemia due to underlying disease and its treatment may undergo blood transfusion prior to treatment in order to meet this criteria)
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| E.4 | Principal exclusion criteria |
1.Patient with well recognized subsets of carcinoma of unknown primary site where treatments directed towards a defined tumor type, or surgery, alternatively radiotherapy, can be advised:
• women with adenocarcinoma involving only axillary lymph nodes
• women with papillary serous carcinoma of the peritoneum
• women with adenocarcinoma with positive staining for estrogen receptor or progesterone receptor (ER/PR)
• young men (< 45 yrs old) with poorly differentiated carcinoma consistent with an extragonadal germ cell tumor (carcinoma involving mediastinium or retroperitonium, or elevated levels of beta-human chorionic gonadotropin or alpha-fetoprotein)
• men with bone metastases and/or adenocarcinoma, and abnormally elevated prostate specific antigen (PSA) in their plasma
• patients with squamous cell carcinoma involving only cervical lymph nodes, or inguinal lymph nodes
• patients with neuroendocrine carcinomas determined according to standard pathology diagnosis procedures, including stains
• patients with potentially completely resectable metastatic disease, or disease which can be adequately treated with radiotherapy only.
2.Patients with brain or meningeal metastases. Note, patients with adequately treated brain metastases, e.g. surgically resected, or adequately controlled by radiotherapy, with no residual neurological symptoms due to metastases and no steroid treatment required, can be enrolled. If clinical suspicion, adequate investigations should be performed to rule out brain metastases or meningeal involvement.
3.Prior systemic anti-tumor therapy, including chemotherapy administered in association to radiotherapy for sensitization, for the carcinoma of unknown primary. Note, prior radiotherapy or surgery is allowed provided treatment was completed at least 4 weeks before randomization.
4.Treatment with investigational agents, including non-anti-tumor agents, within the last 4 weeks before randomization.
5.Co-existing active severe infection or any co-existing medical condition assessed by the investigator as likely to interfere with trial procedures.
6.Significant cardiovascular disease (New York Heart Association Class III or IV cardiac disease), myocardial infarction within the past 6 months, unstable angina, unstable arrhythmia or a need for anti-arrhythmic therapy (use of medication to control heart rate in patients with atrial fibrillation is allowed, if stable medication for at least last month prior to randomization and medication not listed as causing Torsade de Points, see Section 13.2, Appendix B), or evidence of acute ischemia on ECG.
7.Marked baseline prolongation of QT/QTc interval, i.e., demonstration of a QTc interval > 450 msec; Long QT Syndrome; the required use of concomitant medication that may cause Torsade de Pointes (See Section 13.2, Appendix B).
8.Altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures.
9.History of a previous malignancy within 5 years with the exception of non-metastatic non-melanoma skin cancer or cervical carcinoma in situ. Prior systemic therapy for other malignancy completed at least 5 years before randomization is allowed.
10.Known hypersensitivity to either platinum compounds or paclitaxel, or any components of the study medications, and inability for desensitization.
11.Known infection with HIV, or known active Hepatitis B or C infection.
12.Peripheral neuropathy ≥ Grade 2.
13.Pregnant, or lactating, females.
14.Women of childbearing age and potential who are not willing to use effective contraception during the study and until 30 days after last dose of study drug. Male patients or male patients who have female partners of childbearing age and potential who are not willing to use effective contraception during the study and until 30 days after last dose of study drug. Highly effective methods of birth control are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomised partner.
15.Patients that are not affiliated with social security (study centers in France only).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy study variable is Progression Free Survival (PFS). This is defined as the time from the date of randomization to the day of documented disease progression or death due to any cause. It will be based on tumor assessments made according to the RECIST criteria. All tumor assessments obtained during the study, i.e. both treatment phase and follow-up phase, will be included in this analysis. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Overall survival
objective response rate according to RECIST criteria
time to response
duration of response
time to progression |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 | No |
| 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 |
| Denmark |
| France |
| Germany |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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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| Patients will be treated with carboplatin+paclitaxel iv +belinostat iv and oral every 3 weeks for up to 6 cycles followed by oral belinostat till disease progression or unmanagable treatment related toxicities or patient wishes to stop or carboplatin+paclitaxel iv every 3 weeks for up to 6 cycles till disease progression or unmanagable treatment related toxicities or patient wishes to stop. Patients are followed till disease progression and survival follow up for up to 5 years |
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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 | 6 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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