Combination Of DTIC Research Articles

ANTIINTEGRIN AVG3 SAV-RGD AS COMBINANT FOR DTIC WITH HUMAN AMELANOTIC SKIN MELANOMA

Introduction. The avB3 integrin (cell adhesion molecule) plays the role of the receptor, including, metalloproteinase matrix 2, involved in melanoma metastasis. We have been characterized as an antimelanoma original anti-integrin agent SAV-RGD (lyo-SAV-RGD), specifically binding to melanoma cells by means of the Arg-Gly-Asp tripeptide. More significant inhibited effect was obtained on amelanotic human skin melanoma MeWo. Accordingly, the experimental evaluation of the effectiveness of lyo-SAV-RGD in combination with the «gold» standard of antimelanoma chemotherapy dacarbazine (DTIC) is relevant. Objective: a comparative study of the combination of DTIC+lyo-SAV-RGD on the model of pigmented melanoma of human skin MeWo. Material and methods. The model of human skin melanoma MeWo in vivo/in vitro: s.c. xenografts in Balb/c nude mice, sensitive to DTIC cell line MeWo and obtained prospectively stable subline MeWo/DTIC was used. In vitro experiments the time of cell doubling in both models was determined and the individual range of agent concentrations was studied. Therapy with DTIC+lyo-SAV-RGD were administered in simultaneously sequentially, first the single 150 mg/kg DTIC, then lyo-SAV-RGD 9-fold course in the total dose of 900 mg/kg (the first dose is doubled). To control of the group with single dose 250 mg/kg of DTIC close to the maximum tolerated dose (MTD). All experiments were performed by standard methods using significant evaluation criteria and adequate statistical processing of the results (p<0.05). Results. For MeWo and MeWo/DTIC cells with a certain prospectively identical doubling time of the doubling time of tumor cells (Tpot) at the level of 23.0±2.3 h and 23.1±1.8 h, DTIC was practically non-cytotoxic, IC50=410±4 g/ml and IC50=860±27 g/ml (IC50<1o0 g/ml). However, the absolute value of the active concentrations of DTIC was significantly less known for murine pigmented melanoma, 1200-1400 g/ ml. Lyo-SAV-RGD, on the contrary, was cytotoxic for both melanoma variants at the same level, IC50=100±3.1 g/ml, and in the range from 1,0 to 100 g/kg caused cell death in direct dependence on the concentration. On s.c. MeWo xenografts DTIC at the dose of 250 mg/kg was effective at T/ C<30% (criterion T/C<42%) with partial death of mice from toxicity. The combination of DTIC+lyo-SAV-RGD showed an identical effect regardless of dose reduction by 40%, T/C=38% (p=0.001). Conclusion. A comparative study on the model of human skin melanoma MeWo revealed in vitro the absence of significant cytotoxicity of DTIC and at the same time cytotoxicity of anti-integrin avB3 lyo-SAV-RGD for MeWo and MeWo/DTIC cells. On xenografts MeWo combined therapy DTIC+lyo-SAV-RGD with dose reduction cytostatic 40% made it possible to obtain the maximum antitumor effect (T/C=38% vs 30%) with improved tolerability. The obtained data suggest that the introduction of anti-integrin avB3 into the scheme with DTIC is advisable to increase the selectivity of cytotoxic action of cytostatics.

Interleukin-2 (IL-2) and 5-(3,3-dimethyle-1-triazeno) imidazole-4-carboxamide (DTIC) for adjuvant therapy in resected high-risk primary and regionally metastatic melanoma.

e21076 Background: High-dose interferon (IFN) and ipilimumab currently are the only approved adjuvant therapies for high-risk melanoma patients. We analyze the recurrence free survival (RFS), overall survival (OS), and toxicity profile of Interleukin-2 (IL-2) and 5-(3,3-Dimethyle-1-Triazeno) Imidazole-4-Carboxamide (DTIC) combination for resected high-risk primary and regionally metastatic melanoma patients as an alternative adjuvant therapy. Methods: Patients with stage IIB, IIC and stage III melanoma that were treated and received adjuvant IL-2/DTIC combination therapy at a single institution in the year 2000 to 2010 were retrospectively reviewed. No evidence of residual disease was noted prior to therapy. Regimen consisted of subcutaneous IL-2 at 12 x 106 units on days 1 through 4 every month and DTIC 750mg/m2 on day 1 of each cycle every 28 days for 6 cycles. Individual medical records were accessed to collect the data and the Kaplan-Meier method was used to estimate RFS and the OS. Results: Of the 112 patients included, all underwent surgery and then received adjuvant treatment. 109 patients were followed and 3 were lost to follow-up. 59% of the patients were male, 41% were female. 79 (70.5%) of the patients were alive at the time of analysis and 57 patients were currently event free. 69 (61.61%) of the patients completed all 6 months of adjuvant combination treatment with 22.3% of the patients requiring DTIC and 15.2% of the patients’ required IL-2 dose reduction. 2-year OS (from the day of surgery) was 92.85% (95% CI of 86.29-96.53) with RFS of 66.31% (95% CI of 56.92-74.49) and 5-year OS was 75.57% (95% CI of 64.72-83.50) with RFS of 53.05% (95% CI of 41.91-62.58). Conclusions: With little improvement in the RFS from IFN and high toxicity profile with ipilimumab, neither of these treatment regimens seem to be an ideal option. In our retrospective analysis, combination therapy with IL-2/DTIC appears to be beneficial and well tolerated as an alternative adjuvant treatment for patients with high-risk melanoma, but this observation requires further prospective validation.

Patient-derived solitary fibrous tumour xenografts predict high sensitivity to doxorubicin/dacarbazine combination confirmed in the clinic and highlight the potential effectiveness of trabectedin or eribulin against this tumour

BackgroundPreclinical models that mimic pathological and molecular features of solitary fibrous tumour (SFT) represent an important tool to select effective regimes and novel compounds to be tested in the clinic. This study was aimed at developing two preclinical models of SFT, assessing their predictive value in the clinic and selecting potential novel effective treatments. Material and methodsTwo dedifferentiated-SFT (D-SFT) models obtained from patients' biopsies were grown in immunodeficient mice. The antitumour activity on these models of doxorubicin, dacarbazine (DTIC), ifosfamide (monotherapy or combination), trabectedin and eribulin was tested. Twelve SFT patients were treated with doxorubicin and DTIC. Response by RECIST, progression-free survival and overall survival were retrospectively evaluated, distinguishing malignant-SFT (M-SFT) and D-SFT. ResultsTwo D-SFT patient-derived xenografts (PDXs) that represent the first available preclinical in vivo models of SFT were developed and characterised. Doxorubicin/DTIC, DTIC/ifosfamide, doxorubicin/ifosfamide combinations consistently induced better antitumour activity than the single-agents. Particularly, doxorubicin/DTIC combination caused a max tumour volume inhibition >80% in both models. Doxorubicin/DTIC combo showed activity also in the case-series. Best RECIST responses were: 6 responses (M-SFT = 2 of 7, D-SFT = 4 of 5), 1 stable disease, 5 progressions, with a 6-month median progression-free survival (M-SFT = 6, D-SFT = 10 months). The PDXs were very sensitive to trabectedin and eribulin. ConclusionDoxorubicin plus DTIC combination was effective in our two D-SFT mice models and appeared to be active also in the clinic, especially in high-grade D-SFT patients. Among additional drugs tested in the PDXs, trabectedin and eribulin were highly effective, providing a rational to test these drugs in D-SFT patients.

72IN - Which Systemic Therapies Should Be Combined to Immunotherapy?

ABSTRACT Melanoma treatment by T cell checkpoint blockade (TcCB), e.g. anti-CTLA-4, PD-1, or PD-L1 mAbs, has largely contributed to the 2013 breakthrough of immunotherapy in medical science. In contrast to targeted therapies with high response rates, usually of short duration, immunotherapy benefits smaller groups of patients, but in case of response, these could be long-term and possibly curative. This raises the question whether and which systemic combination with TcCB can increase the response rate and subsequent the survival of melanoma patients. Several groups of systemic therapies have been tested/are currently tested in combination with TcCB: chemotherapy, angiogenesis inhibitors, targeted therapy, and immune modulators. Aside the reduction of tumor load (to bridge the time till onset of the immune response) several rationals have been postulated for the combination of TcCB with systemic therapies, e.g. induction of immunogenic cell death, synergistic breakdown of tumor vasculature, reduction of intra-tumor immune-inhibitory cells (Treg, MDSC), increased MHC and subsequent tumor antigen expression, reduced expression of T cell checkpoint molecules, and induction or broadening of the tumor specific T cell repertoire. So far most of the ideas are based on pre-clinical observations and are tested in phase 1/2 trials. Only the combination of DTIC and ipilimumab has been tested in a phase 3 trial. Unfortunately the missing comparator arm of single agent ipilimumab hampers the judgement of the net benefit of adding chemotherapy to CTLA-4 blockade. A phase 1 study testing the concurrent combination of selective BRAF inhibition (vemurafenib) and CTLA-4 blockade (ipilimumab) was closed for accrual due to unexpected toxicity. Testing combinations of targeting the MAPK pathway and TcCB inhibitiors at different schemes or with other compounds are currently underway, e.g. BRAF + /-MEK inhibition in combination with CTLA-4 blockade or BRAF inhibition in combination with PD-L1 blockade. In summary, TcCB is currently the most promising treatment approach in melanoma. Modulation of the tumor microenvironment, immunogenicity of the tumor cells itself, and the T cell repertoire will improve response rates and long-term outcome for patients treated with TcCB. Disclosure: C. Blank: Advisory role for BMS, MSD, Roche, Novartis, and GSK. Research funding from Novartis.

Efficacy of combined axitinib with dacarbazine in a B16F1 melanoma xenograft model

In this study, we evaluated the efficacy and intestinal side effects of the selective inhibitor of vascular endothelial growth factor (VEGF) receptors, axitinib and/or dacarbazine (DTIC), in a B16F1 melanoma xenograft model. C57BL/6 mice were subcutaneously inoculated with B16F1 melanoma cells. The study was randomized into four groups receiving either 0.5% carboxyl methylcellulose, DTIC, axitinib or a combination of DTIC and axitinib. When the experimental period was complete, the tumor tissues from each mouse were excised, photographed and weighed. The tumor and intestinal tissues were harvested with 4% paraformaldehyde, and paraffin-embedded sections were prepared for hematoxylin and eosin staining, immunohistochemical staining (with antibody specific to proliferating cell nuclear antibody) and terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling assays. The expression of the VEGF and matrix metalloproteinase 9 genes was analyzed using real-time polymerase chain reaction. No significant benefit to treatment with a combination of axitinib and DTIC, as opposed to axitinib alone, was observed; however, the combined treatment did not enhance the level of enteritis compared with that observed in the axitinb group. In addition, axitinib, as a single agent, demonstrated an improved treatment efficacy compared with DTIC. Therefore, axitinib represents a potential novel, efficient and safe anticancer agent, suggesting a possible use for this schedule in treating melanomas that are less sensitive to DTIC.

Phase III randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) versus DTIC alone as first-line treatment in patients with unresectable stage III or IV melanoma.

LBA5 Background: IPI monotherapy (3mg/kg) improved overall survival (OS) in a phase III study of previously treated, unresectable or metastatic melanoma. Current study in 1st line metastatic melanoma evaluates combination of DTIC (a global standard of care) plus IPI. Methods: In this double-blind phase 3 study, patients (pts) with metastatic melanoma, ECOG PS 0/1, and no prior therapy for advanced disease, were randomized 1:1 to IPI (10 mg/kg) + DTIC (850 mg/m2) or placebo + DTIC (850 mg/m2) at Wks 1, 4, 7, 10 followed by DTIC q3 wks through Wk 22 (induction). Eligible pts received IPI or placebo q12 wks as maintenance. Primary endpoint was OS; 2-sided log-rank test was performed, stratified by baseline M stage and ECOG PS. Results: Of 502 pts, 56% had M1c disease, 40% elevated LDH, and 26% adjuvant therapy. 37% in IPI + DTIC and 65% in DTIC alone arms received 4 induction doses. A significant improvement in OS (HR=0.72; P=0.0009) and higher estimated 1, 2 and 3 yr survival rates were seen with IPI + DTIC (Table). 56% in IPI +DTIC (n=247) and 27% in DTIC alone (n=251) arms had grade 3/4 adverse events (AEs, regardless of attribution), including: elevated ALT (22% vs 1%); diarrhea (4% vs 0%); rash (1% vs 0%). No intestinal perforations or hypophysitis were noted. There were no drug-related deaths in IPI + DTIC and one in DTIC alone arm [gastrointestinal (GI) hemorrhage]. Conclusions: IPI (10mg/kg) + DTIC significantly improved OS in 1st line metastatic melanoma vs DTIC alone; durable survival and objective responses were noted in some pts after follow-up for up to 4yrs. Type of AEs was consistent with prior IPI studies; however, frequencies of some AEs differed with a higher transaminitis and lower diarrhea/colitis/ GI perforation rates than expected. No drug-related deaths were noted in IPI arm. OS benefit of IPI is confirmed in treatment-naive metastatic melanoma. [Table: see text]

Combination of DTIC and peptide-vaccination elicit a renewal of high-avidity late-differentiated T-cell clones in melanoma patients (156.6)

Abstract Combination of chemo/immunotherapy to increase the effectiveness of the antitumor immune responses associated with a clinical efficacy is an attractive antitumor strategy. We have recently reported that the administration of dacarbazine (DTIC) one day before peptide (Melan-A and gp100)-vaccination in disease-free melanoma patients increases the number of peptide-specific effector-memory CD8+ lymphocytes. Notably, patients treated with DTIC before vaccination, showing a longer survival, display a progressive enhancement of TCR repertoire diversity of Melan-A+ CD8+ clones, accompanied by the maintenance of high-avidity, whereas patients treated with vaccine alone showed a reduction of TCR repertoire diversity and a decline of their tumor lytic activity. To study the phenotype and the functional lytic activity of CD8+ T-cell clones in association with their renewal rate we have analyzed the expression of CD28 and CD27 co-stimulatory molecules, in both Melan-A- and gp100-specific T-cell clones, isolated before and at different times after the treatments. We found newly recruited clones with high-lytic activity and highly-differentiated phenotype only after the combined therapy. Studies are in progress to define the role of replicative senescence in the continuous renewal induced by the combined therapy, by studying activity and regulation of telomerase in endogenous-induced or vaccine-driven clones, in correlation with their different phenotype and anti-tumor lytic capability.

Platelet-activating factor receptor (PAF-R)-dependent pathways control tumour growth and tumour response to chemotherapy

BackgroundPhagocytosis of apoptotic cells by macrophages induces a suppressor phenotype. Previous data from our group suggested that this occurs via Platelet-activating factor receptor (PAF-R)-mediated pathways. In the present study, we investigated the impact of apoptotic cell inoculation or induction by a chemotherapeutic agent (dacarbazine, DTIC) on tumour growth, microenvironmental parameters and survival, and the effect of treatment with a PAF-R antagonist (WEB2170). These studies were performed in murine tumours: Ehrlich Ascitis Tumour (EAT) and B16F10 melanoma.MethodsTumour growth was assessed by direct counting of EAT cells in the ascitis or by measuring the volume of the solid tumour. Parameters of the tumour microenvironment, such as the frequency of cells expressing cyclo-oxygenase-2 (COX-2), caspase-3 and galectin-3, and microvascular density, were determined by immunohistochemistry. Levels of vascular endothelium growth factor (VEGF) and prostaglandin E2 (PGE2) were determined by ELISA, and levels of nitric oxide (NO) by Griess reaction. PAF-R expression was analysed by immunohistochemistry and flow cytometry.ResultsInoculation of apoptotic cells before EAT implantation stimulated tumour growth. This effect was reversed by in vivo pre-treatment with WEB2170. This treatment also reduced tumour growth and modified the microenvironment by reducing PGE2, VEGF and NO production. In B16F10 melanoma, WEB2170 alone or in association with DTIC significantly reduced tumour volume. Survival of the tumour-bearing mice was not affected by WEB2170 treatment but was significantly improved by the combination of DTIC with WEB2170. Tumour microenvironment elements were among the targets of the combination therapy since the relative frequency of COX-2 and galectin-3 positive cells and the microvascular density within the tumour mass were significantly reduced by treatment with WEB2170 or DTIC alone or in combination. Antibodies to PAF-R stained the cells from inside the tumour, but not the tumour cells grown in vitro. At the tissue level, a few cells (probably macrophages) stained positively with antibodies to PAF-R.ConclusionsWe suggest that PAF-R-dependent pathways are activated during experimental tumour growth, modifying the microenvironment and the phenotype of the tumour macrophages in such a way as to favour tumour growth. Combination therapy with a PAF-R antagonist and a chemotherapeutic drug may represent a new and promising strategy for the treatment of some tumours.

Malignant Melanoma Therapy by Chemotherapy and Autoimmunity Induced by Cytokine

The aim of this study was to evaluate the effect of combining dacarbazine (DTIC) and granulocyte/macrophage colony-stimulating factor (GM-CSF) with interleukin-2 (IL-2) in patients with advanced malignant melanoma. Twenty-seven (27) patients with advanced malignant melanoma received dacarbazine (500 mg/m(2)/days 1-2, intravenously), GM-CSF (175 ug/m(2)/days 3-6, subcutaneously), and interleukin-2 (400 MIU/m(2)/days 7-10, subcutaneously). Each treatment cycle required 21 days to completion. Time to progression was 7-11 months. The total effective rate was 44.4%, and the combination of chemotherapy, GM-CSF, and IL-2 had low toxicity. The combination of DTIC with GM-CSF and IL-2 is feasible and possibly efficacious for clinical use.

Combined treatment with pegylated interferon–α‐2a and dacarbazine in patients with advanced metastatic melanoma

AbstractBACKGROUND.Dacarbazine (DTIC) and pegylated interferon (IFN)–α‐2a have both demonstrated some efficacy as single agents in metastatic melanoma. To the authors' knowledge, the current study is the first to test a combination of these 2 agents in a phase 2 trial.METHODS.Twenty–eight patients with stage IV melanoma without brain metastases were treated with DTIC (at a dose of 850 mg/m2 every 3 weeks) combined with weekly pegylated IFN–α‐2a at a dose of 180 μg. The study was initiated to evaluate the efficacy and tolerability of the combination. The primary study endpoint was objective response.RESULTS.Twenty–five patients were evaluable for response. Two patients (8.0%) achieved a complete response that continued for >480 days and 746 days, respectively. Four patients (16.0%) demonstrated a partial response, and another patient experienced stable disease. Six of 7 nonprogressive patients had either not received treatment or had not developed disease progression during adjuvant IFN treatment for stage II/III disease. The median duration of response was 236 days, the median progression‐free survival was 56 days, and the overall survival time was 403 days. Few grade 3 toxicities and only 1 grade 4 toxicity were observed (according to National Cancer Institute Common Toxicity Criteria).CONCLUSIONS.The combination of DTIC and pegylated IFN–α‐2a was found to be well tolerated in patients with metastatic melanoma. The response rate of 24%, including 2 long‐lasting complete responses, is encouraging, but must be confirmed in larger trials. Cancer 2008. © 2008 American Cancer Society.

Influence of therapy on the antioxidant status in patients with melanoma

Some anticancer drugs can result in increased production of reactive oxygen species (ROS). Alkylating agents are the most frequently used drugs in chemotherapeutic regimens for the treatment of malignant melanoma. It is known that triazenes exhibit in vivo activity by alkylation of nucleic acids and proteins, but there is no data about ROS formation during oxidative metabolism. Single agents of most interest for treatment of malignant melanomas include 5-(3,3-dimethyltriazene-1-yl)-imidazole-4-carboxamide (DTIC) and nitrosoureas such as 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), but complete response to these drugs is rare. The present study aimed to determine whether an oxidative stress occurs during the clinical course of melanoma and the influence of therapy on the antioxidant status of patients with melanoma. For this purpose, we investigated plasma concentrations of MDA as indices of the levels of lipid peroxidation products. In addition, we studied the activities of the antioxidant enzymes superoxide dismutases (SOD) and catalase (CAT) in patients with melanoma before any treatment, after surgical removal of melanoma, and after chemotherapy with DTIC or in combination with CCNU of the operated patients. Twenty one patients with melanoma were studied. Patients were operated prior to chemotherapy. After recovery for 10-20 days postoperatively, they were studied again for MDA, SOD and CAT activity. The patients were divided into two groups according to the chemotherapy (3-7 treatment cycles): with DTIC-given orally daily for 5 days, every 3 weeks as a single 2200 mg/kg dose and with the combination-DTIC (the same dose) + CCNU-administered orally at a dosage of 120 mg/m(2) once every 40 days in accordance with protocols, approved by the Bulgarian Ministry of Health. The total amount of lipid peroxidation products in plasma was assayed. Plasma levels of MDA and CAT activity were significantly higher, and erythrocyte SOD activity significantly lower, in patients with melanoma, than in control healthy volunteers (P < 0.0001). Ten to twenty days after surgery, oxidative stress decreased but levels of MDA increased as a result of therapy. Important sources of increased ROS production may be the monocytes, phagocytosis of tumour cells and the cancer tissues. Plasma MDA in patients treated with DTIC + CCNU were significantly higher (P < 0.001), but erythrocyte SOD statistically lower (P < 0.00001), compared with patients treated with DTIC only. However, a combination of DTIC + CCNU did not attenuate oxidative stress, or reduced antioxidant status. Patients treated with this combination are at bigger risk of oxidative injury. Therefore, this disturbance might be due to augmented generation of toxic ROS, possibly from the metabolism of CCNU. Increased oxidative stress follows an imbalance in antioxidant defence in non-treated patients with melanoma. The impaired antioxidant system favours accumulation of ROS, which may promote the cancer process. After complete removal of melanoma tissues, oxidative stress decreased. The antioxidant status of melanoma patients operated on was influenced by the different chemotherapeutic regimens used and may play an important role in the response. Patients on DTIC + CCNU are at higher risk of oxidative injury. This drug combination probably exerts its toxic activity by ROS, which could be products of the metabolism of CCNU.

CPG 7909, a TLR9 agonist immunomodulator in metastatic melanoma: A randomized phase II trial comparing two doses and in combination with DTIC

7526 Background: Malignant melanoma is widely accepted as an immunologically responsive tumor. Expectations for major clinical benefit with treatment by interferons or from biochemotherapy trials have not been met, and the prognosis for patients (pts) with metastatic disease remains poor. A new synthetic chemical immunomodulator, CPG 7909 (ProMune), is now being studied in a large randomized phase II trial based on single agent tumor activity in metastatic pts. CPG 7909 is a non-antisense oligodeoxynucleotide which activates plasmacytoid dendritic cells and B cells through targeted agonism of the Toll-like receptor 9 (TLR9) and is a strong activator of both innate and adaptive immunity. Methods: 184 pts with the diagnosis of metastatic melanoma were enrolled in 48 sites. Pts were randomized into 4 arms: CPG 7909 10 mg, CPG 7909 40 mg, CPG 7909 40 mg in combination with DTIC, or DTIC alone. All CPG 7909 was administered by weekly S.C. injection in multiple sites. DTIC (850 mg/m2) was administered I.V. every 21 days. Treatment was continued until disease progression. Randomization was stratified for presence or absence of liver metastases. The primary study endpoint was response by RECIST criteria, with follow up for survival. Results: Enrollment has been completed and treatment is ongoing. These S.C. doses of CPG 7909 are generally well tolerated and do not complicate DTIC treatment. Preliminary response assessments on 92 pts include 4 PRs in the combination arm vs. 2 PRs on DTIC, 1 PR on CPG 7909 10 mg and none on CPG 7909 40 mg. 57 pts had disease progression at or before the 9 week (3rd cycle) evaluation. Adverse events included transient injection site reactions, fever and arthralgias. Three SAE’s included a case of an anaphylactoid reaction (wheezing and angioedema within two minutes), a vasovagal reaction with hypotension, and one sudden death following an acute MI. PK and PD analyses are ongoing. Conclusions: Subcutaneous administration of CPG 7909 at doses up to 40mg once weekly is safe and well tolerated by most pts. A new combination of DTIC with a potent TLR9 agonist may show a better response than does DTIC alone in metastatic melanoma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Coley Pharmaceutical Group Coley Pharmaceutical Group Coley Pharmaceutical Group

Effects of interferon-alpha, verapamil and dacarbazine in the treatment of advanced malignant melanoma.

Treatment of patients with metastatic melanoma with either dacarbazine (DTIC) or interferon-alpha (IFNalpha) as single drugs, or in combination, results in a response rate of approximately 15-20%. This study evaluated the activity and toxicity following treatment with a combination of DTIC, IFNalpha2b and verapamil (VPL). Thirty patients with disseminated metastatic melanoma received DTIC 250 mg/m(2) on days 1-5 of a 4 week schedule, IFNalpha2b 3 MIU on days 1-5 each week, and VPL 80 mg three times a day throughout the cycle, until either disease progression or serious toxicity was observed. Among the 28 evaluable patients, there were four complete responses (CRs), five partial responses (PRs) and eight patients with stable disease (SD). The overall response rate (CR + PR) was 32%. Two patients with a CR were long-term survivors (45 and 34 months) and a third is still in complete remission after 49 months. The fourth CR patient relapsed and died with progressive brain metastases after 8 months. Among the eight patients with SD, one survived for 22 months and another for 34 months. Despite one toxic death, these results suggest that this treatment regimen is well tolerated and seems to be more effective than DTIC alone in a subset of patients. A controlled randomized study would be required to determine the value of adding VPL and IFNalpha2b to DTIC.

Phase II Study of Cisplatin and Dacarbazine for Metastatic Colorectal Carcinoma Resistant to 5-Fluorouracil

Twenty-six patients with metastatic colorectal cancer were given cisplatin (CDDP) and dacarbazine (DTIC). Patients who relapsed while receiving adjuvant 5-fluorouracil (FU) or had 5-FU-resistant metastatic disease were included. Median age was 52 years and the male-to-female ratio was 1. Performance status (ECOG) was 3 in 5 patients and 0–2 in the remainder. CDDP (20 mg/m²/day i.v.) and DTIC were given (250 mg/m²/day i.v.) on days 1–5. The treatment was repeated every 3 weeks until disease progression. Total response rate was 19.2% (95% confidence interval: 4.5–34.3%) with one clinical complete response (3.8%) and 4 partial responses (15.4%). Median response duration was 5 months. Median survival for the whole group and for responders was 6 and 8 months, respectively. In conclusion, CDDP + DTIC combination has modest activity in patients with colorectal cancer resistant to 5-FU treatment.

Systemic therapy in melanoma.

The patient with surgically incurable melanoma presents a difficult problem for the medical oncologist. Single chemotherapeutic agents at conventional doses produce bona fide but infrequent remissions. The most active single agent for the treatment of metastatic melanoma is dacarbazine (DTIC). Until recently, combinations of drugs yielded no real improvement over treatment with the individual components. The combination of DTIC + carmustine (BCNU) + cisplatin + tamoxifen (the "Dartmouth regimen") appears to be more effective than DTIC alone, but prospective randomized trials comparing the two are still in progress. The contribution of tamoxifen to the observed results continues to be evaluated. Biological agents, such as interferon and interleukin-2, have lower overall response rates compared to chemotherapy regimens, but response duration appears to be longer. Chemotherapy combined with biotherapy offers the promise of higher response rates and long-term durable remissions. The results from high-dose regimens that use autologous bone marrow or peripheral stem cell support have not been sufficient to justify the added toxicity. Although advanced melanoma often is not curable with systemic therapy, the considered use of currently available regimens can induce clinically significant remissions and, possibly, prolong life in some patients.

Porcine splenic peptides (Polyerga) decrease the number of experimental lung metastases in mice

Preparations of splenic peptides under the name of Polyerga are being tested in numerous experimental immunomodulating and antitumorous models and are also used during supportive treatment of tumorous patients. Further, the incidence of experimental lung metastases of melanoma cells in mice was significantly reduced if we used Polyerga preparations. The aim of our investigation was to determine whether Polyerga is active directly against tumor cells or whether its activity is manifested by modulating immune and other possible abilities of the organism. To clarify the problem glycopeptides containing Polyerga were incubated with melanoma B16F10 cells in vitro and the plating efficiency of these cells determined when cultivated in medium, or in medium with different doses of the same Polyerga preparation. The cells preincubated in medium only reacted to the addition of increasing doses of Polyerga, 150 pg or more, by raising colonies number. However, 24-h incubation of melanoma cells in the presence of 150 micrograms of Polyerga per ml significantly reduced the number of tumor cell colonies in comparison to the corresponding cell cultures previously not exposed to Polyerga. These in vitro studies were extended to in vivo application using C57B1/GoZgr mice injected i.v. with melanoma cells pretreated with Polyerga in vitro or previously not treated. A group of the treated mice was further injected i.p. with Polyerga. All the mice were killed at a particular time and the number of lung nodules determined. A significant difference to the control values was noticed in each group that used Polyerga, regardless of the exposure of melanoma cells to Polyerga in vitro, in vivo or to combined treatment. The efficiency of Polyerga application 7 days following i.v. injection of control melanoma cells (cultivated in medium only) when the nodules already exist, was further evaluated in a combined treatment using DTIC, a drug of choice in melanomas. The smallest incidence of experimental lung metastases was observed in the group exposed to the combination of DTIC and Polyerga. Polyerga preparation is thus active against melanoma cells, particularly in vivo and if combined with chemotherapy.

Combination chemotherapy for disseminated malignant melanoma.

Malignant melanoma, once disseminated, is associated with very short survival times and has proven highly resistant to systemic therapy. Although many chemotherapeutic agents can produce small response rates in these patients, the most consistent responses occur with dacarbazine (DTIC). Numerous combination regimens, with and without DTIC, have been tested against disseminated melanoma, with varying and inconsistent outcomes. The most encouraging results have occurred with the combination of DTIC, cisplatin, BCNU and tamoxifen. The use of high-dose chemotherapy with and without autologous bone marrow support and the addition of biologic agents such as inteferon-alpha and interleukin-2 to conventional chemotherapy have also been actively investigated. This paper reviews the various approaches taken against disseminated melanoma employing systemic chemotherapy.

Biochemotherapy with thymosin α1, interleukin-2 and dacarbazine in patients with metastatic melanoma: Clinical and immunological effects

DTIC and interleukin-2 (IL-2), as single agents, have a limited anti-tumor activity in patients with metastatic melanoma. Experimentally, thymosin alpha 1 (TA1) may modulate the action of IL-2. We investigated the clinical and immunological effects of a combination with these three agents. Forty-six patients with measurable metastatic melanoma were treated with DTIC 850 mg IV on day 1, TA1 2 mg s.c. on days 4 to 7, and IL-2 18 MU/m2/d by continuous intravenous infusion on days 8 to 12. Cycles were repeated every 3 weeks. Objective responses were obtained in 15 (36%) of 42 evaluable patients (CI at 95%: 22%-50%). Two patients experienced complete responses, and stable disease was observed in five. The median time to progression was 5.5 months and median survival was 11 months. Side effects were predominantly caused by IL-2. Treatment was tolerated reasonably well, and there was no overlapping toxicity or interference between chemotherapy and biotherapy. Baseline sCD4 levels seem to correlate to tumor burden. Patients benefiting from treatment had lower sCD4 and higher sCD8 than did progressing patients. The combination of DTIC + TA1 + IL-2 is active in the treatment of advanced melanoma, with acceptable toxicity. However, even more active regimens are needed, and the interactions between thymic hormones and cytokines should be further explored.

Treatment of metastatic malignant melanoma with dacarbazine, vindesine and cisplatin.

Twenty-seven patients with disseminated malignant melanoma were treated monthly with cisplatin (CDDP) 120 mg m-2 on day 1, vindesine (VDS) 3 mg m-2 on day 2 and dacarbazine (DTIC) 250 mg m-2 on days 2-6. None of them had received prior chemotherapy. All patients are evaluable for response and toxicity. There were five (19%) complete (CR) and seven (26%) partial (PR) responses for a total response rate of 45%. We conclude that the combination of DTIC, VDS and CDDP is capable of producing a relatively high rate of response in patients with advanced metastatic malignant melanoma, but responses are short.

Evaluation of cis-platinum and DTIC combination chemotherapy in disseminated melanoma. A Southwest Oncology Group Study.

The development of disseminated melanoma is associated with an extremely poor prognosis. Use of a variety of chemotherapy agents alone and in combination has yielded response rates of only 10-30%. Surgery and radiation therapy play a useful role in palliative treatment, but have little or no value in the treatment of disseminated disease. In order to evaluate the response of disseminated malignant melanoma to combination chemotherapy with cis-platinum and 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide (DTIC), a phase II pilot study was developed and conducted at Oregon Health Sciences University. Thirty patients were treated from January 1983 to October 1986 and evaluated. There were two complete responses (7%) and nine partial responses (30%) for a total response rate of 37%. The median duration of response was 31 weeks. This response rate is higher than has been previously achieved with DTIC and cis-platinum, or with other drugs alone or in combination. Severe (grade 3) renal, neurologic, and hematologic toxicity was seen in four of 30, three of 30, and ten of 30 patients, respectively.