Phase I Dose-Escalation Study of SCB01A,a Microtubule Inhibitor with Vascular Disrupting Activity,in Patients with Advanced Solid Tumors

Lessons Learned

• SCB01A is a novel microtubule inhibitor with vascular disrupting activity.
• This first‐in‐human study demonstrated SCB01A safety, pharmacokinetics, and preliminary antitumor activity.
• SCB01A is safe and well tolerated in patients with advanced solid malignancies with manageable neurotoxicity.

BackgroundSCB01A, a novel microtubule inhibitor, has vascular disrupting activity.MethodsIn this phase I dose‐escalation and extension study, patients with advanced solid tumors were administered intravenous SCB01A infusions for 3 hours once every 21 days. Rapid titration and a 3 + 3 design escalated the dose from 2 mg/m² to the maximum tolerated dose (MTD) based on dose‐limiting toxicity (DLT). SCB01A‐induced cellular neurotoxicity was evaluated in dorsal root ganglion cells. The primary endpoint was MTD. Safety, pharmacokinetics (PK), and tumor response were secondary endpoints.ResultsTreatment‐related adverse events included anemia, nausea, vomiting, fatigue, fever, and peripheral sensorimotor neuropathy. DLTs included grade 4 elevated creatine phosphokinase (CPK) in the 4 mg/m² cohort; grade 3 gastric hemorrhage in the 6.5 mg/m² cohort; grade 2 thromboembolic event in the 24 mg/m² cohort; and grade 3 peripheral sensorimotor neuropathy, grade 3 elevated aspartate aminotransferase, and grade 3 hypertension in the 32 mg/m² cohort. The MTD was 24 mg/m², and average half‐life was ~2.5 hours. The area under the curve‐dose response relationship was linear. Nineteen subjects were stable after two cycles. The longest treatment lasted 24 cycles. SCB01A‐induced neurotoxicity was reversible in vitro.ConclusionThe MTD of SCB01A was 24 mg/m² every 21 days; it is safe and tolerable in patients with solid tumors.     

A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma

Lessons Learned

• A PHY906 and capecitabine combination could be effective as a salvage therapy for patients with hepatocellular carcinoma (HCC) previously treated with multiple systemic therapies.
• This traditional Chinese medicine formulation can work with Western cancer chemotherapeutic agents to improve clinical outcomes or alleviate side effects for patients with advanced HCC.

BackgroundThis study aimed to evaluate efficacy and safety of capecitabine combined with a PHY906 (a pharmaceutical‐grade formulation of four traditional Chinese herbs) in the treatment of advanced hepatocellular carcinoma (HCC) in Asian patients who were positive for hepatitis B virus (HBV).MethodsThis study was an open‐label, phase II safety and efficacy clinical trial of PHY906 and capecitabine in patients with advanced HCC. Patients received 750 mg/m² capecitabine b.i.d. 14 days plus 800 mg of PHY906 b.i.d. on days 1–4 and days 8–11 every 21‐day cycle. The primary endpoint was 6‐month survival rate, and secondary endpoints were progression‐free survival, overall survival, disease control rate, and safety.ResultsThirty‐nine subjects completed the study with a 46.2% stable disease rate. The median progression‐free survival was 1.5 months, and median overall survival (mOS) was 6 months with a 51.3% 6‐month survival rate. The most common adverse events included lower hemoglobin, diarrhea, pain, abdomen (not otherwise specified), fatigue, increased aspartate aminotransferase, and bilirubin. Patients who (a) had not received previous chemotherapies or targeted therapy or (b) had lower starting alpha‐fetoprotein (AFP) levels or (c) had HBV infection showed better clinical outcome.ConclusionOur data showed that PHY906 increases the therapeutic index of capecitabine by enhancing its antitumor activity and reduces its toxicity profile in advanced HCC.     

Effects of a novel tylophorine analog on collagen-induced arthritis through inhibition of the innate immune response

OBJECTIVE: To test the effects of a novel tylophorine analog, DCB 3503, on the prevention and treatment of collagen-induced arthritis (CIA) and to elucidate its underlying mechanisms. METHODS: DBA/1J mice were immunized with type II collagen, and in some cases, lipopolysaccharide (LPS) was used to boost the development of arthritis. DCB 3503 was injected intraperitoneally before or after the onset of CIA. Mice were monitored to assess the effects of DCB 3503 on the clinical severity of the disease, and pathologic changes in the joints were examined histologically. Levels of tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta) in serum and joint tissues were measured by enzyme-linked immunosorbent assay and by cytometric bead array analysis. The effect of DCB 3503 on LPS-induced proinflammatory cytokines from bone marrow-derived dendritic cells was determined by flow cytometry. RESULTS: DCB 3503 significantly suppressed the development and progression of CIA. Moreover, DCB 3503 completely blocked the LPS-triggered acceleration of joint inflammation and destruction. Consistent with its effects in vivo, DCB 3503 significantly suppressed the synthesis of proinflammatory cytokines in inflamed joints as well as cytokine synthesis by macrophages examined ex vivo. Treatment also reduced the levels of inflammatory cytokines (IL-6, IL-12, TNFalpha, and monocyte chemotactic protein 1) produced by bone marrow-derived dendritic cells in vitro. However, DCB 3503 showed no direct effects on T cell proliferation and B cell antibody response. CONCLUSION: Because of its ability to specifically suppress innate immune responses, DCB 3503 may be a novel therapeutic agent for inflammatory arthritis in humans.     

Phase I study of biweekly gemcitabine followed by oxaliplatin and simplified 48-h infusion of fluorouracil/leucovorin for advanced pancreatic cancer

OBJECTIVES: To evaluate the feasibility and maximal tolerated dose (MTD) of oxaliplatin of a triplet regimen consisting of gemcitabine, oxaliplatin and infusional fluorouracil (5-FU)/leucovorin (LV) (GOFL) for advanced pancreatic cancer. PATIENTS AND METHODS: Patients with histologically proven metastatic or unresectable, locally advanced pancreatic adenocarcinoma were eligible to take part in the study. The treatment consisted of fixed-rate infusion (10 mg/m2/minute) of 800 mg/m2 gemcitabine followed by 2-h infusion of oxaliplatin and then 48-h infusion of 5-FU/LV day 1 and day 15 every 4 weeks. The oxaliplatin would be evaluated at three dose levels, 65, 75 and 85 mg/m2. RESULTS: A total of 15 patients were enrolled at three dose levels. Dose-limiting toxicity of neutropenic fever and grade 4 thrombocytopenia occurred in one of each six patients at oxaliplatin dose level of 65 mg/m2 and 85 mg/m2, respectively. The MTD of oxaliplatin for this combination was 85 mg/m2. After a median four cycles of treatment, grade 3/4 neutropenia occurred in 46.7% of patients and thrombocytopenia in 13.3%. Non-hematological toxicities were generally of grade 1/2. Objective tumor response was observed in five patients (33.3%, 95% confidence interval, 6.3-60.4%). CONCLUSION: Biweekly GOFL is a feasible regimen for advanced pancreatic cancer. For further phase II studies, the recommended dose of oxaliplatin is 85 mg/m2.     

Comparison of different diagnostic methods for lupus pleuritis and pericarditis: a prospective three-year study.

BACKGROUND AND PURPOSE: Pleural or pericardial effusions, or both, are commonly encountered, but the differential diagnosis is sometimes difficult. We evaluated the diagnostic value of effusion immunofluorescent antinuclear antibody (ANA) titer, systemic lupus erythematosus (SLE) latex agglutination slide test, and cytologic LE cell examination in patients with pleural and/or pericardial effusions of various etiologies. METHODS: A total of 153 pleural and/or pericardial effusion specimens were collected by aspiration from 152 patients (14 SLE and 138 non-SLE patients). All specimens were sent for routine biochemistry testing, determination of ANA titer, SLE latex agglutination slide test, and LE cell examination. RESULTS: Ten of the 14 SLE patients had lupus serositis and all of them had high ANA titers (> or = 1:160) in their effusions. SLE latex and LE cell tests were positive in seven and eight patients with lupus serositis, respectively. The remaining four SLE patients with effusion of etiologies other than lupus serositis had low or negative effusion ANA titers. Among the non-SLE patients, 29 of 112 patients (26%) with pleural effusion and six of 26 patients (23%) with pericardial effusion had positive ANA tests (> or = 1:40). None of them had a positive SLE latex or LE cell test result. Thirteen of the 138 non-SLE patients (11%) had high effusion ANA titers (> or = 1:160). Effusion in 11 of 13 non-SLE patients (85%) was due to malignancy. CONCLUSIONS: Effusion ANA titer detection is a very sensitive but nonspecific test for the diagnosis of lupus serositis. SLE latex and cytologic LE cell tests can aid in the differential diagnosis as complementary tools. The specificity, positive and negative predictive values of these two tests are excellent for the diagnosis of lupus serositis.     

Combination chemotherapy and photodynamic therapy of targetable N-(2-hydroxypropyl)methacrylamide copolymer-doxorubicin/mesochlorin e(6)-OV-TL 16 antibody immunoconjugates.

The aim of this study was to evaluate the combination chemotherapy and photodynamic therapy of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-bound doxorubicin (DOX) and mesochlorin e(6) (Mce(6)) targeted with an OV-TL 16 monoclonal antibody (P-DOX-Ab and P-Mce(6)-Ab, respectively) in nude mice bearing human ovarian OVCAR-3 carcinoma xenografts. P-DOX-Ab and P-Mce(6)-Ab were synthesized by first conjugating DOX or Mce(6) to an HPMA copolymer precursor (Mw=21000), then reacting with OV-TL 16 antibody. The immunoconjugates were purified by size exclusion chromatography on Superose 6 column and analyzed. The Mce(6) concentration in tissues was determined by a fluorescence assay. Eighteen hours after administration, the tumors received a light dose of 220 J/cm(2) from a KTP 650-nm dye-laser. P-DOX-Ab and P-Mce(6)-Ab had polymer:drug:protein weight ratios of 32:3:62 and 26:2:72, corresponding to polymer:drug:protein molecular ratios of approximately 4:14:1 and 3:8:1, respectively. The biodistribution results indicated that the percentage of total administered dose of Mce(6) in tumors reached approximately 1% for the nontargeted conjugate at 18 h after administration, while that of P-Mce(6)-Ab was approximately 13 times higher. Nude mice bearing OVCAR-3 xenografts that received one i.v. dose of P-DOX-Ab (2.2 mg/kg DOX equivalent) and P-Mce(6)-Ab (1.5 mg/kg Mce(6) equivalent) with light irradiation achieved a xenograft cure rate of more than 60%. The incorporation of OV-TL 16 antibody dramatically enhanced the accumulation in tumors with a concomitant increase in the therapeutic efficacy of P-DOX-Ab and P-Mce(6)-Ab in combination therapy, which may probably be attributed to both antibody targeting and enhanced permeability and retention (EPR) effects.