Phase II trial of chlorozotocin in malignant melanoma, breast cancer, and other solid tumors

We have conducted a broad phase II clinical trial of chlorozotocin in 74 patients including 28 with malignant melanoma, 18 with breast cancer, nine with non-Hodgkin's lymphoma, six with nonseminomatous testicular cancer, five with ovarian cancer, four with sarcoma, three with non-beta islet cell carcinoma of the pancreas, and one with anaplastic carcinoma of the thyroid. Objective responses were noted only in 15% of the patients with melanoma and in 11% of the patients with non-Hodgkin's lymphoma. Significant leukopenia and thrombocytopenia were observed only in previously treated patients. Chlorozotocin does not appear to offer clinically significant advantages over other currently available nitrosoureas.     

Alpha-2-interferon/melphalan/prednisone in previously untreated patients with multiple myeloma: a phase I-II trial

Alpha-2-interferon (IFN) has demonstrable activity in advanced, relapsing, or refractory multiple myeloma. Because of the in vitro synergism between the IFNs and cytotoxic agents, we conducted a trial of 30 previously untreated patients with multiple myeloma utilizing various doses of alpha-2-IFN in combination with standard oral doses of melphalan and prednisone. The combination was well-tolerated without unusual or unexpected toxic effects. The limiting toxicity included dose-related myelosuppression, and alpha-2-IFN induced flu-like symptoms and fatigue. Response was seen in at least as many patients as would be expected with melphalan and prednisone alone. The maximal tolerated dose for a phase II-III trial was 5.0 X 10(6) IU/m2 of alpha-2-IFN in combination with standard doses of melphalan and prednisone. Future trials should utilize this dose of alpha-2-IFN with dose de-escalation according to tolerance.     

Oral cladribine for B-cell chronic lymphocytic leukaemia: report of a phase II trial with a 3-d, 3-weekly schedule in untreated and pretreated patients, and a long-term follow-up of 126 previously untreated patients

A phase II study was undertaken to evaluate the efficacy and toxicity of a new schedule of cladribine administration (10 mg/m2 orally daily for 3 d every 3 weeks) in 107 patients with B-cell chronic lymphocytic leukaemia (CLL). To minimize toxicity, treatment withdrawal criteria were defined. The results of the 63 previously untreated patients were retrospectively compared with 63 from an earlier study using a 5-d monthly schedule. The compiled data were analysed for prognostic factors for survival. No significant difference regarding response were seen in the two cohorts of the 126 previously untreated patients. The complete response (CR), nodular partial response (nPR) and partial response (PR) rates were 15%, 21% and 41%. Quality of response had no impact on survival. The 3- and 5-year overall survival for previously untreated patients was 73% and 58%, respectively, with a median follow-up of 54 months. Pretreatment haemoglobin <11.0 g/dl and elevated beta-2-microglobulin had a negative influence on survival. Major infections occurred in 21% of patients in the 3-d study compared with 35% in the 5-d study. The overall response (OR) and CR rates in the 40 previously treated patients were 34% and 5% respectively. Median overall survival was 24 months and median progression-free survival for responding patients was 14 months. Cladribine used as a single agent is an effective treatment with an acceptable safety profile for pretreated and untreated B-CLL. The achievement of complete remission was not a prerequisite for long-term survival.     

Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the Cytokine Working Group

PURPOSE: To evaluate the antitumor effects and toxicities of whole brain irradiation (WBI) with temozolomide (TMZ) administered by prolonged oral dosing in patients with melanoma metastatic to the brain. BACKGROUND: Patients with melanoma metastatic to the central nervous system (CNS) have an extremely poor prognosis and appear to benefit little from WBI. TMZ is an alkylating agent chemically similar to dacarbazine (DTIC) with good oral bioavailability and CNS penetration. TMZ has broad preclinical antitumor activity which in melanoma is comparable to that of DTIC. The combination of TMZ and WBI may provide enhanced antitumor activity against CNS metastasis from melanoma. PATIENTS AND METHODS: Patients with measurable CNS metastases with or without systemic disease were treated with WBI, 30 Gray over ten fractions (days 1-5 and 8-12). TMZ, 75 mg small middle dotm(2 small middle dot)day, was started on day 1, continued daily for 6 weeks and repeated every 10 weeks. RESULTS: Thirty-one patients were treated. There was one CNS complete response of 4.5 months and two CNS partial responses of 2 months and 7 months duration; the latter patient also had a 4-month complete remission of systemic metastases. Toxicities were limited to a single episode of grade 3 transaminase elevation and two episodes of grade 3 neutropenia, one complicated by fatal sepsis. The median progression-free interval for both CNS and extracranial sites was 2 months (range 1 week-11 months), and median survival 6 months (range 2-12 months). CONCLUSIONS: WBI has lower than expected activity in CNS metastasis of malignant melanoma. Although TMZ can be safely administered with WBI, the combination has limited anti-tumor activity.     

Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial

The efficacy of bendamustine versus chlorambucil in a phase III trial of previously untreated patients with Binet stage B/C chronic lymphocytic leukaemia (CLL) was re‐evaluated after a median observation time of 54 months in May 2010. Overall survival (OS) was analysed for the first time. At follow‐up, investigator‐assessed complete response (CR) rate (21·0% vs 10·8%), median progression‐free survival (21·2 vs 8·8 months; P < 0·0001; hazard ratio 2·83) and time to next treatment (31·7 vs 10·1 months; P < 0·0001) were improved for bendamustine over chlorambucil. OS was not different between groups for all patients or those ≤65 years, >65 years, responders and non‐responders. However, patients with objective response or a CR experienced a significantly longer OS than non‐responders or those without a CR. Significantly more patients on chlorambucil progressed to second/further lines of treatment compared with those on bendamustine (78·3% vs 63·6%; P = 0·004). The benefits of bendamustine over chlorambucil were achieved without reducing quality of life. In conclusion, bendamustine is significantly more effective than chlorambucil in previously untreated CLL patients, with the achievement of a CR or objective response appearing to prolong OS. Bendamustine should be considered as a preferred first‐line option over chlorambucil for CLL patients ineligible for fludarabine, cyclophosphamide and rituximab.     

Phase 1B, randomized, double-blind, dose-escalation trial of CPG 10101 in patients with chronic hepatitis C virus

CPG 10101, a synthetic oligodeoxynucleotide (ODN), is a toll-like receptor 9 (TLR9) agonist with antiviral and immunomodulatory properties that could potentially influence chronic infection with HCV. In this multicenter Phase 1b trial, 60 HCV-positive patients (50 genotype 1 HCV) were randomized and received either placebo or CPG 10101 at 0.25, 1, 4, 10, or 20 mg subcutaneously (SC) twice weekly for 4 weeks or at 0.5 or 0.75 mg/kg SC once weekly for 4 weeks. Dose-dependent cytokine induction was observed after administration of CPG 10101. At 24 hours after administering the highest dose of 0.75 mg/kg CPG 10101, interferon (IFN)-gamma-inducible protein 10 (IP-10) had a mean increase over baseline levels (+/-SD) of 15,057 (+/-9769) pg/ml (P < 0.01, compared to placebo); IFN-alpha had a 106 (+/-63.3) pg/ml increase (P < 0.01); and 2'5'-oligoadenylate synthetase (OAS) had a 163 (+/-120.6) pmol/dl increase (P < 0.01). Decreases in HCV RNA also were dose-dependent, with the greatest group geometric mean maximum reduction of 1.69 +/- 0.618 log(10) (P < 0.05) observed in the 0.75 mg/kg dose group. Decreases >/=1 log(10) were seen in 22 of 40 patients who received >/=1 mg CPG 10101, with 3 patients exceeding a 2.5-log(10) reduction. CPG 10101 was well tolerated, and adverse events were consistent with CPG 10101's mechanism of action. Conclusion: In this Phase 1 study, CPG 10101 was associated with dose-dependent increases in markers of immune activation and decreases in HCV RNA levels. The data support further clinical studies of CPG 10101 for treating chronic HCV infection.     

Repeated administration of short infusions of bendamustine: a phase I study in patients with advanced progressive solid tumours

Purpose: The cytotoxic agent bendamustine combines a purine-like benzimidazol and bifunctionally alkylating nitrogen mustard group. The drug has clinical antitumour activity in lymphoma, myeloma and breast cancer. In earlier dose-finding studies, the clinically tolerated dose for single-bolus bendamustine was 215 mg/m²; for fractionated therapy on 4 consecutive days it was 85 mg/m². Anticholinergic symptoms, myelosuppression and cardiac dysrhythmia were dose-limiting. Our trial was designed to define the maximum tolerated dose of a short infusion schedule and to establish a recommended dose for ongoing and future clinical studies. Methods: Patients with refractory malignant tumours qualified for the trial after written informed consent had been obtained. Bendamustine was given as a 30-min iv. infusion on days 1 and 8 of a 4 week cycle, with a starting dose of 100 mg/m² and an increment per group of 20 mg/m². Results: Nineteen patients (13 male, 6 female; median age 57 years, range 37–74 years) were treated for one to two cycles with up to 180 mg/m² bendamustine. At 160 mg/m², fatigue grade 3 (NCI Common Toxicity Criteria) and dryness of the mouth grade 3 occurred in 2 patients, diarrhoea grade 3 in 1 patient; another patient with a history of myocardial infarction and arrhythmia developed a reversible total atrioventricular block after the first administration of 160 mg/m² bendamustine. Other events, such as nausea/vomiting, loss of appetite, fever or chills, were not dose-limiting. Haematological toxicity was mild, except for sudden and long-lasting grade 3–4 lymphocytopenia, which occurred in all treatment cycles. Opportunistic infections were not observed. Conclusions: The maximum tolerated dose of a days-1 and -8 schedule of bendamustine, given as a 30-min i.v. infusion, is 160 mg/m²; mouth dryness and fatigue are dose-limiting. The recommended dose for future trials is 140 mg/m². Received: 11 May 1999 / Accepted: 18 July 1999     

Epoetin beta therapy in patients with solid tumours

Anaemia is a common occurrence in patients with cancer, resulting in symptoms such as fatigue that have a profound impact on quality of life. Anaemia is also associated with poor treatment outcome and overall survival. Epoetin beta, a recombinant human erythropoietin that has the same structure and function as the endogenous hormone, is an effective and safe treatment of cancer-related anaemia. Various studies in patients with solid tumours have shown that this agent effectively increases haemoglobin levels and reduces the need for emergency blood transfusions regardless of the type of concomitantly administered chemotherapy. Epoetin beta also improves the quality of life of anaemic patients with cancer, decreasing fatigue and improving the ability to perform usual daily activities. In addition, epoetin beta prevents severe anaemia and reduces transfusion requirements in patients with a high-risk of developing anaemia during chemotherapy, such as those receiving platinum-based regimens. A meta-analysis of epoetin beta trials showed that epoetin beta has no negative impact on survival or thrombosis-related survival and may reduce the risk of tumour progression in patients with solid or lymphoid malignancies. Another study has shown epoetin beta to be equally effective when administered once weekly or three times weekly. Therefore, epoetin beta offers an effective, safe and convenient therapy for the management of anaemia in patients with cancer.