A phase I/II study of KW-2478, an Hsp90 inhibitor, in combination with bortezomib in patients with relapsed/refractory multiple myeloma.

BACKGROUND: KW-2478 is a novel non-ansamycin Hsp90 inhibitor with modest single-agent activity in relapsed/refractory myeloma but which shows synergistic antimyeloma activity with bortezomib (BTZ) in preclinical studies. This study determined the safety, preliminary clinical activity, and pharmacokinetics of KW-2478, an Hsp90 inhibitor, in combination with BTZ in patients with relapsed/refractory multiple myeloma (MM). METHODS: Phase I dose escalation determined the recommended phase II dose (RP2D) of KW-2478 plus BTZ, which was then used during phase II. RESULTS: The maximum tolerated dose was not reached during phase I and the RP2D was KW-2478 175 mg m-2 plus BTZ 1.3 mg m-2 on days 1, 4, 8, and 11 every 3 weeks. In the efficacy evaluable phase I/II population treated at the RP2D (n=79), the objective response rate was 39.2% (95% confidence interval: 28.4-50.9%), clinical benefit rate 51.9% (40.4-63.3%), median progression-free survival 6.7 (5.9-not reached (NR)) months, and median duration of response 5.5 (4.9-NR) months. In the phase I/II safety population (n=95), the most frequently observed treatment-related grade 3/4 adverse events were diarrhoea, fatigue, and neutropenia (each in 7.4% of patients), and nausea and thrombocytopenia (each in 5.3%). CONCLUSIONS: KW-2478 plus BTZ was well tolerated with no apparent overlapping toxicity in patients with relapsed/refractory MM. The antimyeloma activity of KW-2478 in combination with BTZ as scheduled in this trial appeared relatively modest; however, the good tolerability of the combination would support further exploration of alternate dosing schedules and combinations.

Mipsagargin, a novel thapsigargin-based PSMA-activated prodrug: results of a first-in-man phase I clinical trial in patients with refractory, advanced or metastatic solid tumours.

BACKGROUND: Mipsagargin (G-202; (8-O-(12-aminododecanoyl)-8-O-debutanoyl thapsigargin)-Asp-γ-Glu-γ-Glu-γ-GluGluOH)) is a novel thapsigargin-based targeted prodrug that is activated by PSMA-mediated cleavage of an inert masking peptide. The active moiety is an inhibitor of the sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA) pump protein that is necessary for cellular viability. We evaluated the safety of mipsagargin in patients with advanced solid tumours and established a recommended phase II dosing (RP2D) regimen. METHODS: Patients with advanced solid tumours received mipsagargin by intravenous infusion on days 1, 2 and 3 of 28-day cycles and were allowed to continue participation in the absence of disease progression or unacceptable toxicity. The dosing began at 1.2 mg m(-2) and was escalated using a modified Fibonacci schema to determine maximally tolerated dose (MTD) with an expansion cohort at the RP2D. Plasma was analysed for mipsagargin pharmacokinetics and response was assessed using RECIST criteria. RESULTS: A total of 44 patients were treated at doses ranging from 1.2 to 88 mg m(-2), including 28 patients in the dose escalation phase and 16 patients in an expansion cohort. One dose-limiting toxicity (DLT; Grade 3 rash) was observed in the dose escalation portion of the study. At 88 mg m(-2), observations of Grade 2 infusion-related reaction (IRR, 2 patients) and Grade 2 creatinine elevation (1 patient) led to declaration of 66.8 mg m(-2) as the recommended phase II dose (RP2D). Across the study, the most common treatment-related adverse events (AEs) were fatigue, rash, nausea, pyrexia and IRR. Two patients developed treatment-related Grade 3 acute renal failure that was reversible during the treatment-free portion of the cycle. To help ameliorate the IRR and creatinine elevations, a RP2D of 40 mg m(-2) on day 1 and 66.8 mg m(-2) on days 2 and 3 with prophylactic premedications and hydration on each day of infusion was established. Clinical response was not observed, but prolonged disease stabilisation was observed in a subset of patients. CONCLUSIONS: Mipsagargin demonstrated an acceptable tolerability and favourable pharmacokinetic profile in patients with solid tumours.

Myelotoxicity of samarium Sm 153 lexidronam in patients receiving prior treatment with chemotherapy or radiotherapy.

BACKGROUND: The effect of prior treatment with radiotherapy and/or chemotherapy on the myelotoxicity of samarium lexidronam (Sm 153) in patients with metastatic bone lesions and bone pain was described. METHODS: Single-institution retrospective chart review of patients receiving Sm 153. The effect of Sm 153 on peripheral white blood cell (WBC), platelet counts, and change from baseline was calculated. RESULTS: The available hematologic data from records of 58 patients receiving 100 treatments with Sm 153 were reviewed. Prior treatment with radiotherapy or chemotherapy had no effect on changes from baseline or median nadir counts for either WBC or platelets when compared with patients not having such prior treatments. Multiple treatments with Sm 153 had no effect on change from baseline in WBC or platelet counts as compared with the initial administration. Median survival following the first dose of Sm 153 was 15 months. CONCLUSIONS: Prior treatment with radiotherapy or chemotherapy did not affect the rates of myelotoxicity. Multiple treatments with samarium Sm 153 lexidronam also had no effect on severity of myelotoxicity with successive courses. Patients with bone predominant metastatic disease may survive for extended periods of time and may safely be treated with multiple modalities of therapy.

Phase II study of trimetrexate, fluorouracil, and leucovorin for advanced colorectal cancer.

PURPOSE: A phase II study to evaluate the response rate and toxicities of a trimetrexate, fluorouracil (5FU), and leucovorin regimen in patients with advanced incurable colorectal cancer. PATIENTS AND METHODS: Thirty-six patients with unresectable or metastatic colorectal cancer who had not been treated for advanced disease received the following chemotherapy regimen weekly for six courses every 8 weeks: trimetrexate 110 mg/m2 intravenously (I.V.) on day 1, leucovorin 200 mg/m2 I.V. on day 2 (24 hours later), 5FU 500 mg/m2 on day 2 immediately following leucovorin, and oral leucovorin 15 mg every 6 hours for seven doses starting 6 hours after 5FU. Patients were treated until progression or unacceptable toxicity. RESULTS: Thirty patients were assessable for response, and all 36 were assessable for toxicity. Two patients (7%) achieved a complete response (CR) and 13 (43%) a partial response (PR), for an overall response (OR) rate of 50% (95% confidence interval [CI], 32% to 68%). Analysis by intent to treat demonstrated a 42% OR rate (95% CI, 26% to 58%). At final analysis, 16 patients were alive. The median survival duration for the entire cohort was 53.4 weeks. Gastrointestinal toxicity was most common, with 21 patients (58%) having grade 3/4 diarrhea and 12 patients (34%) grade 3/4 nausea. Hematologic toxicity was generally low grade, although two patients died of sepsis. CONCLUSION: The combination of trimetrexate with 5FU and leucovorin is active in metastatic colorectal cancer. Gastrointestinal toxicity with this regimen is most prominent, but is manageable.

A trial of IRX-2 in patients with squamous cell carcinomas of the head and neck.

A Phase II trial in 42 patients with squamous cell cancer of the head and neck (H and NSCC) was performed using a combination immunotherapy with 10-20 days of perilymphatic injections of a natural cytokine mixture (NCM: IRX-2; 200 units IL-2 equivalence) preceded by low dose cyclophosphamide (CY; 300 mg/m(2)) and followed by daily oral indomethacin (25 mg t.i.d.) and zinc (65 mg in a multivitamin preparation). Thirty-nine patients underwent subsequent surgical resection and 22 stage IV patients received additional radiotherapy. Forty-two percent were adjudged to have complete and partial clinical responses (>50% tumor reduction); an additional five patients had minor responses for a total of 58%. Comparison of post-treatment biopsies or surgical specimens showed 90% of patients had reduction in tumor area from 79% to 48% (over half of which was fragmented) and increased area of leukocyte infiltration from 9% to 32% (79% of which was lymphoid). The treatment with IRX-2 was not associated with significant side effects and 24 of patients showed improvement in eating, breathing or phonation or reduced pain and bleeding. Fifteen patients with lymphocytopenia (lymphocyte counts [LC] less than or equal to 1500 mm(3)) showed significant increases in LC, CD3+, CD4+ and CD8+ T lymphocytes of 401, 147, 95 and 100/mm(3), respectively. Analysis of outcome of 32 on protocol patients after 36 months versus 32 concurrent institutional H and NSCC controls showed delayed recurrences and significant increases in mean survival time (MST) and survival (p's<0.02). The data document immunotherapy induced regression of H and NSCC with delayed recurrence and improved mean survival time.

The proliferative response to epidermis of hairless mice to full thickness wounds.

The healing of full thickness surgical wounds from 0 to 14 days has been studied in hairless mice. Within 2 days after wounding the surrounding epidermis is thickened and primarily composed of enlarged basophilic cells. The remnants of the hair follicles attached to the epidermis are converted into cords of enlarged basophilic cells. Epidermal thickening is maximum at 7 days. Associated with the epidermal thickening surrounding the wound edge is an increase in the total number of cells in the stratum granulosum and in the stratum spinosum. The number of basal cells does not change. Mitotic activity and mitotic rate increase within 1 day after wounding. Both reach their peaks by approximately 5 to 7 days and then begin to return to control levels. Mitotic duration does not change.

Phase I/II dose-escalation study of liarozole in patients with stage D, hormone-refractory carcinoma of the prostate.

BACKGROUND: Liarozole binds to the cytochrome P-450-dependent hydroxylating enzymes involved in steroid biosynthesis and retinoic acid catabolism. This phase I study investigated the clinical/endocrine toxicity profile of liarozole and determined the maximally tolerated dose (MTD) in hormone-refractory prostate cancer patients. METHODS: Groups of five patients were treated with oral liarozole caplets, starting at 37.5 mg twice daily. The dose was doubled for each subsequent group until the MTD was reached, after which, an additional 18 patients were entered into the MTD-1 dose stratum. The long-term safety of liarozole was assessed based on treatment-emergent signs and symptoms and clinically significant laboratory results. RESULTS: Thirty-eight patients were enrolled. The MTD was determined to be 300 mg twice daily. Side effects that defined the MTD included lethargy, somnolence, body rash, and paresthesias. Two deaths occurred during the trial (pneumonia and myocardial infarction). Four patients had a > 50% decrease in prostate-specific antigen (PSA) levels (two at 150 mg, two at 300 mg). Of nine patients with measurable disease, two had partial responses. CONCLUSIONS: Liarozole was generally well tolerated with no evidence of adrenal insufficiency. Preliminary evidence of activity in this indication was observed based on dose-dependent decreases in PSA levels and improvement in soft-tissue metastasis.