A phase I and pharmacokinetic study of plitidepsin in children with advanced solid tumours: An Innovative Therapies for Children with Cancer (ITCC) study

Geoerger, Birgit; Estlin, Edward J.; Aerts, Isabelle; Kearns, Pamela; Gibson, Brenda; Corradini, Nadège; Doz, François; Lardelli, Pilar; Miguel, Bernardo De; Soto, A.; Prados, R.; Vassal, Gilles

doi:10.1016/j.ejca.2011.10.036

Cited by 31 publications

(25 citation statements)

References 25 publications

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“…In the single-agent Phase I trial in pediatric patients (APL-A-005-02),30 the safety profile was not strikingly different from that in the adult Phase I program, although a slightly higher incidence of grade 3/4 hypersensitivity reactions was observed despite mandatory prophylactic medication.…”

Section: Developmentmentioning

confidence: 93%

“…Most (n=31) discontinued treatment due to disease progression, but six children showed clinical benefit (Table 2). 30…”

Section: Developmentmentioning

confidence: 99%

“…The primary dose-limiting toxicities (DLTs) found in the dose-finding Phase I studies with single-agent plitidepsin were musculoskeletal adverse events (AEs) 26–30,36,41. The most common were myalgia, muscle weakness, and increase in serum CPK (noncardiac fraction) levels.…”

Section: Developmentmentioning

confidence: 99%

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Plitidepsin: design, development, and potential place in therapy

Alonso‐Álvarez

Pardal

Sánchez-Nieto

et al. 2017

DDDT

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Plitidepsin is a cyclic depsipeptide that was first isolated from a Mediterranean marine tunicate (Aplidium albicans) and, at present, is manufactured by total synthesis and commercialized as Aplidin®. Its antitumor activity, observed in preclinical in vitro and in vivo studies has prompted numerous clinical trials to be conducted over the last 17 years, alone or in combination with other anticancer agents. Single-agent plitidepsin has shown limited antitumor activity and a tolerable safety profile in several malignancies, such as noncutaneous peripheral T-cell lymphoma, melanoma, and multiple myeloma. In patients with relapsed or refractory multiple myeloma, plitidepsin activity seems to be enhanced after addition of dexamethasone while remaining well tolerated, and a Phase III trial comparing plitidepsin plus dexamethasone vs dexamethasone alone is underway. Additional studies are required to better define the role of plitidepsin in combination with other active agents in these indications. Results of plitidepsin activity in other hematological malignancies or solid tumors have been disappointing so far. Further studies analyzing its mechanisms of action and potential biomarkers will help select patients who may benefit most from this drug. In this review, we critically analyze the published studies on plitidepsin in hematological malignancies and solid tumors and discuss its current role and future perspectives in treating these malignancies. We also review its design, pharmaceutical data, and mechanism of action.

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Section: Developmentmentioning

confidence: 93%

“…Most (n=31) discontinued treatment due to disease progression, but six children showed clinical benefit (Table 2). 30…”

Section: Developmentmentioning

confidence: 99%

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Plitidepsin: design, development, and potential place in therapy

Alonso‐Álvarez

Pardal

Sánchez-Nieto

et al. 2017

DDDT

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“…Furthermore, there are attempts to parallelize the progressive alignment step [step (iii)] as in [28] and [29]. In [28], the independent pre-aligned pairs along the dendrogram are aligned simultaneously.…”

Section: Introductionmentioning

confidence: 99%

“…This technique gains some speed-up, however, the time complexity of the algorithm remains unchanged since all the pair-wise alignments eventually must be merged together. Another attempt is seen in [29], where Huang's algorithm [25] is used. When an anti-diagonal of a DP alignment matrix in lower tree level in step (iii) is completed, it is distributed immediately to other processors for computing the pair-wise alignment of a higher tree level.…”

Section: Introductionmentioning

confidence: 99%

Parallel progressive multiple sequence alignment on reconfigurable meshes

2011

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BackgroundOne of the most fundamental and challenging tasks in bio-informatics is to identify related sequences and their hidden biological significance. The most popular and proven best practice method to accomplish this task is aligning multiple sequences together. However, multiple sequence alignment is a computing extensive task. In addition, the advancement in DNA/RNA and Protein sequencing techniques has created a vast amount of sequences to be analyzed that exceeding the capability of traditional computing models. Therefore, an effective parallel multiple sequence alignment model capable of resolving these issues is in a great demand.ResultsWe design O(1) run-time solutions for both local and global dynamic programming pair-wise alignment algorithms on reconfigurable mesh computing model. To align m sequences with max length n, we combining the parallel pair-wise dynamic programming solutions with newly designed parallel components. We successfully reduce the progressive multiple sequence alignment algorithm's run-time complexity from O(m × n4) to O(m) using O(m × n3) processing units for scoring schemes that use three distinct values for match/mismatch/gap-extension. The general solution to multiple sequence alignment algorithm takes O(m × n4) processing units and completes in O(m) time.ConclusionsTo our knowledge, this is the first time the progressive multiple sequence alignment algorithm is completely parallelized with O(m) run-time. We also provide a new parallel algorithm for the Longest Common Subsequence (LCS) with O(1) run-time using O(n3) processing units. This is a big improvement over the current best constant-time algorithm that uses O(n4) processing units.

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