CAL-101 in previously treated CLL (dose-finding)

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Comment: This dose-finding study for a single agent shows promising activity

in a population with very high-risk CLL.

Phase I study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol

3‑kinase P110d, in patients with previously treated chronic lymphocytic

leukemia.

http://abstract.asco.org/AbstView_102_83782.html

Abstract:

Background: The class I phosphatidylinositol 3-kinases (PI3Ks) regulate cellular

functions relevant to oncogenesis (targets pathway that contributes to malignant

behavior).

Expression of the PI3K p110δ isoform (PI3Kδ) is restricted to cells of

hematopoietic origin (affects are specific to blood cells). CAL-101 is an

isoform-selective inhibitor of PI3Kδ that induces apoptosis of chronic

lymphocytic leukemia (CLL) cells.

==Methods: This phase I study evaluated CAL-101 in patients with previously

treated hematologic cancers.

CAL-101 was administered orally 1 or 2 times per day (QD or BID) continuously in

28-day cycles, until disease progression or unacceptable toxicity.

Efficacy analyses were based on standard criteria.

==Results:

At data cutoff, the study had enrolled 54 patients with CLL.

Patient characteristics included: median [range] age of 62 [37‑82] years; 82%

males;

72% with refractory disease,

81% with bulky disease,

36% with del(17p), and a

median [range] of prior therapies of 5 [2‑15].

(Very high risk disease)

CAL-101 dose levels were 50 mg, 100 mg, 150 mg, 200 mg, and 350 mg BID; and 300

mg QD. (a dose-finding study)

The median [range] of CAL‑101 treatment cycles was 8 [1-19]. Grade ≥3

adverse events included pneumonia (24%), neutropenia (24%), thrombocytopenia

(7%), neutropenic fever (7%), anemia (6%) and ALT/AST increase (6%).

CAL‑101 reduced lymphadenopathy by ≥50% in 80% of patients.

A transient increase of >50% from baseline in peripheral absolute lymphocyte

counts occurred in 58% of patients.

The overall intention-to-treat response rate by IWCLL 2008 criteria was 26%.

Medians for duration of response and progression-free survival had not been

reached (>11 months), with 46% of patients continuing on treatment.

CAL-101 reduced constitutive overexpression of phospho‑AKT in patient CLL

cells and normalized plasma concentrations of CCL3, CCL4, and CXCL13. PK

analyses showed minimal increases in plasma Cmax and AUC at doses >150 mg BID.

Accrual is ongoing and updated data will be presented. Conclusions: CAL-101, an

oral PI3Kδ-selective inhibitor, shows acceptable safety and promising clinical

activity in heavily pretreated patients with CLL.

Dose‑response assessments support the 150 mg BID dose (the middle dose tested)

for future single-agent and combination chemo/immunotherapy studies.

Patients Against Lymphoma

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