Topotarget is the sponsor of twelve clinical studies which are
or have been conducted with intravenous belinostat either as
monotherapy or in combination with chemotherapy.
In parallel with the IV program, Topotarget is also conducting
one trial with oral belinostat (CLN-9).
Single agent treatment with IV or oral belinostat is conducted
in both solid tumors and hematological malignancies.
Belinostat in combination carboplatin and paclitaxel is being
investigated in patients with CUP, bladder cancer, and ovarian
cancer, with doxorubicin in soft tissue sarcoma, with bortezomib
and prednisone in multiple myeloma, with idarubucin in AML, as well
as with 5-FU in various gastrointestinal tumors.
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CLN-19 (BELIEF)
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PTCL |
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| PXD101-CLN-19 is a pivotal open-label, multicenter, single arm efficacy and safety study in patients with relapsed or refractory peripheral T-cell lymphoma who have failed at least one prior systemic therapy. Approximately 120 patients will be enrolled. Patients will be treated with 1000 mg/m² belinostat administered as a 30 minute IV infusion on days 1-5 of every 3-week cycle until there is disease progression or unmanageable treatment-related toxicities. The primary study endpoint will be objective response rate according to the International Harmonization Project (IHP) revision of the International Working Group (IWG) criteria (Cheson 2007). |
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CLN-17 (Randomized)
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CUP |
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| PXD101-CLN-17 is an open-label, multinational, multicenter, randomized, comparative efficacy and safety study in previously untreated patients with carcinoma of unknown primary. Patients meeting inclusion and exclusion criteria will be randomized to treatment within either of two study groups: Group A: belinostat (1000 mg/m²) administered as a 30 minute IV infusion once daily on days 1, 2 and 3, followed by belinostat 2000 mg (flat dose) administered orally once daily on days 4 and 5, every 3-weeks, in combination with paclitaxel (175 mg/m²) administered as an IV infusion at least one hour following the infusion of belinostat on cycle day 3, and carboplatin (AUC 6) administered as a 30-60 minute IV infusion directly after the paclitaxel administration on cycle day 3. Group B: paclitaxel (175 mg/m²) administered as an IV infusion directly followed by carboplatin (AUC 6) administered as a 30-60 minute IV infusion on cycle day 1 of a 3-weekly cycle. Approximately 44 patients will be randomized to each group (in total 88 patients). Patients will be treated in three week cycles for up to 6 cycles of chemotherapy containing treatment unless there is disease progression or treatment-related toxicities that are not manageable with dose-reduction schemes allowed per protocol or by other appropriate supportive measures. After 6 cycles of treatment, patients in Group A will continue treatment on belinostat monotherapy at a dose of 750 mg (flat dose) administered orally once daily on days 1 to 14, every 3-weeks until disease progression or treatment-related toxicities. Patients in Group B will stop chemotherapy treatment after 6 cycles. Patients with documented progressive disease will be taken off study treatment at time of progression and may be offered 2nd line treatment. The purpose of the trial is to provide an estimate of the hazard ratio of treatment effect, with the primary study endpoint being progression free survival (PFS).
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CLN-9
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Solid tumors or Lymphomas |
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| PXD101-CLN-9 is an ongoing open-label non-randomized, multi-center, dose-escalation phase 1 trial examining dose and schedule of the oral administration of belinostat. The first cohort included 92 patients with refractory solid tumors and to date 21 patients with lymphoma have been included. Through dose escalation of belinostat from 250 to 2000 mg/d and schedules from daily for 28 days to days 1-14 (3-week cycle) and days 1-5 (3-week cycle) recommended dose levels and schedules are being sought. The study completed enrollment in April 2011.
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CLN-14
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Solid tumors with cohort expansion in STS |
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| PXD101-CLN-14 is an open-label non-randomized, multi-center, dose escalation combination treatment Phase 1b/2 trial in patients with refractory solid tumors including sarcomas with an MTD expansion arm in patients with an established diagnosis of soft tissue sarcoma in need of first line chemotherapy and with measurable disease. The primary objectives of the Phase I part of the study is to determine the MTD of belinostat (dose levels examined were 600, 800 and 1000 mg/m2 /d x5) administered in combination with doxorubicin (dose levels examined 50 and 75 mg/m2 on d 5) in 3-week cycle. The study is currently enrolling patients in the Phase 2 portion. |
| Completed |
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TT20
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Solid tumors |
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| TT20, the first trial of belinostat in man, was an open-label, non-randomized, multicenter, dose escalation Phase 1 trial. Its primary objective was to determine the safety, toxicity, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of belinostat in patients with cancer refractory to standard therapy or for which no standard therapy exists. Belinostat was administered as a 30-minute intravenous (IV) infusion on Days 1 to 5 every three weeks. The trial included 46 evaluable patients and showed that belinostat was well tolerated with a remarkable lack of bone marrow toxicity. MTD of belinostat in this study was determined to be 1000 mg/m² administered on Days 1-5 in a 21 day cycle. The trial also demonstrated that belinostat could be administered orally. A paper summarizing the study data has been published (Steele 2008). |
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TT30
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Hematologic malignancies |
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| TT30 was an open-label, non-randomized, multicenter, dose escalation Phase 1 trial in 16 patients carried out in parallel to the above mentioned TT20 trial, but in patients with malignant blood diseases (myeloma, lymphoma, chronic lymphocytic leukemia). The same dose and schedule as used in TT20 proved to be well tolerated also in patients with haematological diseases and the dose recommended for future studies (the MTD) was determined to 1000 mg/m² administered on Days 1-5 in a 21 day cycle. An article summarizing the study data has been published (Gimsing 2008). |
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301-G
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Advanced myeloma |
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| PXD101-301-G was an open-label non-randomized, multicenter Phase 2 trial. The primary objective of the study was to assess the efficacy of belinostat in patients with advanced myeloma who had failed at least two prior lines of therapy. The study also evaluated the combination treatment of belinostat with dexamethasone (40 mg on Days 2-5 and 10-13 in a 21 day cycle) in patients who had progressed or not responded to belinostat monotherapy treatment. 25 patients were included, 9 had stable disease on monotherapy, ten patients received the combination with dexamethasone and four achieved objective response (2 PR, 2 MR). Reduction of serum M-component was seen in ten patients. |
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CLN-4
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Solid tumors |
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| PXD101-CLN-4 was an open-label non-randomized, dose escalation combination treatment Phase 1b trial in patients with histologically confirmed, measurable solid tumors refractory to standard therapy. The primary objectives of the study were to determine the MTD of belinostat administered in combination with 5-FU, and to assess the effect of belinostat on expression of the enzyme level of thymidylate synthase, a 5-FU target in vivo, in the tumor tissue. 35 patients were included in the study. Belinostat was administered as a 30-minute intravenous (IV) infusion once daily on Days 1 to 5 every three weeks and from treatment cycle 2 combined with 5-FU administered as a 96-hour continuous infusion starting Day 2. The recommended doses were determined to be belinostat 1000 mg/m²/day on Day 1 to 5, and 5-FU 750 mg/m²/24-hours for 96-hours continuous infusion. Belinostat monotherapy was shown to down-regulate thymidylate synthase in tumors from patients where samples were available. |
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CLN-5
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Multiple myeloma |
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| PXD101-CLN-5 was an open-label Phase IB/II study to assess safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity of PXD101 in combination with bortezomib (Velcade®) in patients with relapsed, refractory multiple myeloma. A total of up to 45 patients is planned for study enrollment, with ~ 30 patients in the dose escalation arm and 15 patients in the MTD expansion arm. Patients will be administered PXD101 IV (30 min infusion) daily on Days 1-5 and with bortezomib IV (bolus, 3 5 sec push) on days 1, 4, 8, and 11, in 21-day cycles. PXD101 infusion will start 1 hour after bortezomib administration. The study was stopped due to poor recruitment. Further exploration of this combination is done in the NCI sponsored trial #7281 |
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CLN-6
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CTCL and PTCL |
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| PXD101-CLN-6 was an open-label non-randomized, multi-center Phase 2 trial. The primary objective was to assess the efficacy of belinostat treatment (1000 mg/m2/dx5 q 3 weeks) as measured by response rate using the severity-weighted assessment tool or the response criteria of Cheson et al. in patients with verified diagnosis of cutaneous T-cell lymphoma (CTCL) or peripheral T-cell lymphoma (PTCL), who have failed at least one line of prior systemic therapy. 50 patients were enrolled, responses were seen in both patient groups, follow-up is still ongoing. |
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CLN-8/040
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Solid tumors with cohort expansion in A) recurrent ovarian cancer and B) refractory bladder cancer |
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| PXD101-CLN-8/PXD101-040-EU was an open-label non-randomized, multi-center, dose escalation combination treatment Phase 1b/2 trial. The first phase 1 part included 23 patients with refractory solid tumors. Through dose escalation of belinostat from 600 to 800 and to 1000 mg/m2 the study demonstrated that full dose of belinostat (1000 mg/m2) could be tolerated in combination with standard doses of carboplatin [target area-under-the-curve (AUC) of 5 on Day 3 and paclitaxel (175 mg/m² over 3 hours on Day 3)]. This combination and dose level was then used in an MTD expansion of the study in 35 female patients with recurrent ovarian carcinoma including patients with platinum resistant tumors. The combination proved tolerable and highly effective: complete or partial remission was seen in 43% of the patients and the progression-free survival was from 1 to 23 months with a median of 5 months. Responses were seen both in platinum-sensitive and platinum-resistant disease. The same combination and dose level of belinostat with carboplatin and paclitaxel was also used in another MTD phase 2 expansion of the study in 15 patients with refractory bladder cancer. Promising activity was noted with a 29% objective response rate (CR+PR) and furthermore prolonged disease stabilization in the remaining evaluable patients. While the studies described above used the standard 30 minute infusion of belinostat, an additional cohort of 7 patients had a 3-hour and 6-hour continuous IV administration schedule for belinostat (doses and schedules of the combination otherwise unchanged as compared with the schedule described above). The 3 and 6 hour alternative administration schedule was shown to be well tolerated. This finding allows flexibility in the dosing of belinostat and lays the ground for more prolonged infusions as in study CLN-15. |
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CLN-15
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AML |
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| PXD101-CLN-15 was an open-label non-randomized, multi-center, dose escalation combination treatment Phase 1b/2 trial in patients with AML not suitable for standard intensive therapy. The primary objectives of the study were to evaluate the tolerability and preliminary activity of two schedules of belinostat in combination with idarubicin. Schedule A: belinostat Day 1 to 5 once daily 30-minute intravenous infusions in a 3-week cycle, in combination with idarubicin administered IV on Day 4-5 of each cycle. The belinostat dose was fixed at 1000 mg/m²/day and the idarubicin dose escalated in four steps from 5 mg/m² delivered Day 5 to 10 mg/m² delivered Day 4 and Day 5. The rationale for Schedule B was that non-clinical studies had indicated increased anti-neoplastic potential for belinostat by continuous exposure for 24 or 48 hours. Belinostat was therefore administered by prolonged intravenous infusions with dose steps from 25 mg/m²/24h for 24-hours to 1000 mg/m²/24h for 48-hours. Evaluation of the study is still ongoing but preliminary results from the dose escalation in 18 patients in regimen A will recommend a full dose of belinostat (1000 mg/m2 x 5d) in combination with idarubicin 10 mg/m2 on days 4 and 5. The escalation in schedule B (23 patients) resulted in a dose level of belinostat 1000 mg/m2 /d continuous iv infusion for 48 h in combination with idarubicin 7.5 mg/m2/d on days 1 and 2 being the highest recommended dose. Both schedules of the combination led to pronounced anti-leukemic effect as evidenced by reduction in blast % and a preliminary objective response rate of 24% (CR +PR). |
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CLN-16
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Relapsed or refractory Muliple Myeloma |
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| This study was an open-label non-randomized Phase II study to assess anti-tumor activity and safety of belinostat in combination with bortezomib (Velcade®) in multiple myeloma patients refractory to or relapsed from at least one prior bortezomib-containing regimen. The drug doses was be 600 mg/m2 belinostat plus 1.0 mg/m2 bortezomib (study Part A), and 1000 mg/m2 belinostat plus 1.0 mg/m2 bortezomib (study Part B). The dosing schedule will be the same in both Part A and Part B. Subjects will be administered belinostat (30 min IV infusion) on days 1-5, and bortezomib (3 5 sec IV push) on days 1, 4, 8 and 11, of a 3-week cycle. Belinostat infusion will start approximately 1 hour after bortezomib administration. The study was stopped due to poor recruitment. Further exploration of this combination is done in the NCI sponsored trial #7281 |
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