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Biomedical subjects

C R Franks

Publications and source records attributed to C R Franks.

At least 55 records · Page 3Linked to original sources
PubMed1990

Interleukin-2 in combination with interferon-alpha in disseminated malignant melanoma and advanced renal cell carcinoma. A phase I/II study.

In vitro, the combination of interleukin-2 (Il-2) with interferon-alpha (IFN-alpha) seems to act synergistically on the generation of lymphokine activated killer (LAK) cells. Due to this fact two clinical trials with the combination of Il-2 and IFN-alpha were initiated in malignant melanoma (MM) and renal cell cancer (RCC). Patients with disseminated MM were treated by a sequential application of 10 x 10(6) U/m2 rIFN-alpha 2b s.c. on days 1-7 followed by continuous intravenous infusion of 3 x 10(6) U/m2 rIl-2 on days 8-13 and 15-20. After a pause of 4 weeks the cycle was repeated. In advanced or disseminated RCC, the patients were treated with a daily alternating scheme of 10 x 10(6) U/m2 rIFN-alpha and rIl-2 as 1 h infusion 1 x /day for 14 days. The rIl-2 escalates intra- and interindividually beginning with a dose of 3 x 10(6) U/m2. The cycles were repeated after a pause of 3 and 4 weeks, respectively. The preliminary results show that the schedules are practicable and that the toxicity of the combination of rIl-2 and IFN-alpha does not accumulate. Within the MM group 3/11 evaluable patients achieved partial remission and 2/11 stable disease. In the RCC-group 2/5 evaluable patients achieved partial remission and 2/5 had stable disease so far.

Carcinoma, Renal Cell↗
PubMed1990

Interleukin 2 immunotherapy in children with neuroblastoma after high-dose chemotherapy and autologous bone marrow transplantation.

Four children with persistent neuroblastoma after marrow ablative chemoradiotherapy and autologous bone marrow transplantation received continuous infusion of recombinant interleukin 2, 75 to 120 days after the graft. Recombinant interleukin 2 therapy did not induce any major or nonreversible toxicity, hematological toxicity in particular. One patient entered complete remission for 9 months and a second patient had a long-lasting normalization of urinary catecholamine metabolites with more than 50% regression of bone marrow metastases (8 months). In three children, recombinant interleukin 2 and a second patient entered complete remission for 9 months therapy was followed by major increase and activation of circulating natural killer cells which amounted to 80% of the circulating mononuclear cells.

Bone Marrow Transplantation↗
PubMed1990

Functional and immunophenotypic modifications induced by interleukin-2 did not predict response to therapy in patients with renal cell carcinoma.

Twenty-five patients with renal cell carcinoma were treated with continuous infusion of IL-2 (3 x 10(6) units/m2/day) with or without lymphokine-activated killer (LAK) cells; 5 responded to therapy. Functional and immunophenotypic modifications of the peripheral blood lymphocytes (PBLs) did not predict response to therapy. Systemic administration of interleukin-2 (IL-2) during 5 days caused a preferential proliferation of natural killer (NK) cells, although CD4+ T cells remained the predominant circulating population, in particular in three of the five responding patients. The IL-2 low-affinity receptor was induced only on CD4+ T cells. B cells did not proliferate and immunoglobulin levels were not modified by IL-2. In the peripheral blood, the NK function increased but the LAK function in vivo remained low. The T-cell proliferative response in mixed lymphocyte cultures (MLCs) decreased after therapy. Four days of ex vivo culture of PBLs with IL-2 did not modify T and NK distributions, but increased the coexpression of CD8 on NK cells and NKH1 density; it decreased the coexpression of CD16 and induced LAK cell function. Three weeks after the end of the first course of therapy and before the second course was started, all immunological parameters returned to baseline levels, except the T-cell proliferative response in MLCs. The second course of IL-2 therapy induced the same modifications as the first one, with the exception of a higher CD4+ T-cell proliferation.

Adult↗
PubMed1990

Subcutaneous interleukin-2 and interferon-alpha 2b in patients with metastatic renal cell cancer: the German outpatient experience.

A phase II clinical trial was conducted using subcutaneous recombinant human interleukin-2 (rIL-2, EuroCetus) and subcutaneous interferon-alpha 2b (rIFN-alpha 2b, Essex) in patients with advanced cancer. Safety and tolerance of this outpatient regimen were assessed in 17 patients with progressive metastatic renal carcinoma, 14 of whom were evaluable for clinical response to combined rIL-2 and rIFN-alpha 2b. In this study, rIL-2 was administered every 12 hours, at 1.5 million (Cetus) U/m2 on days 1 and 2, followed by 0.3 million U/m2 5 days per week for 6 consecutive weeks. Concomitantly, rIFN-alpha 2b was given as 5 million U/m2 three times weekly for 6 consecutive weeks. Patients presenting with stable or regressive disease after 6 weeks of rIL-2 and rIFN-alpha 2b (11 of 14) were scheduled to repeat combination therapy. After one treatment cycle, five of 14 patients presented with partial remission; two of these patients achieved complete regression of metastatic lesions. After therapy, six patients have been in stable disease for up to 8 months. toxicity of this regimen was moderate, with local inflammation of the injection sites, grade I-II (World Health Organization criteria) fevers, chills, malaise, nausea and/or vomiting, and anorexia in 70% to 100% of patients treated. After 6 weeks of rIL-2 and rIFN-alpha 2b, laboratory evidence of treatment-related hypothyroidism and hyperthyroidism was obtained in one and four patients, respectively. Immunogenicity of sc rIL-2 was mostly limited to the development of nonneutralizing antibodies that occurred in approximately 40% of patients. None of the patients exhibited antibodies specific to rIFN-alpha 2b.

Ambulatory Care↗
PubMed1990

Low-dose subcutaneous recombinant interleukin-2 in advanced human malignancy: a phase II outpatient study.

Recombinant interleukin-2 (rIL-2; EuroCetus, Amsterdam, Netherlands) was studied in an outpatient phase II trial in 14 patients with progressive metastatic renal carcinoma, malignant melanoma, and colorectal cancer. Escalating doses of rIL-2 were administered as subcutaneous bolus every 12 hours, starting at 0.3 million U/m2/d. A 100% dose increase occurred at weekly intervals, up to a maximum of 2.4 million U/m2/d. Responding patients or patients with stable disease after 4 weeks of rIL-2 (n = 9) were continued on maintenance therapy at 1.8 million U/m2 of rIL-2 administered once weekly. After 12 weeks of therapy, one renal cell cancer patient had a partial regression in lung metastases. Bolus injection of rIL-2 (1.2 million U/m2) resulted in peak serum levels of 25 to 30 U/ml. Toxicity of this regimen was moderate, with local inflammation at the injection sites, grade I-II (World Health Organization) malaise, nausea and/or vomiting, and fevers in 70% to 100% of patients treated. Thyroid dysfunction was observed in 10 patients receiving subcutaneous rIL-2; four of these patients had laboratory evidence of hyperthyroidism, and one had hypothyroidism. rIL-2-induced toxicity reversed spontaneously after cessation of treatment. In all patients receiving rIL-2, a dose-dependent increase in peripheral blood lymphocyte and eosinophil counts was noted, with a mean of 2.6 and 3.8 x 1,000/microliters after 4 weeks of therapy; mean lymphocyte and eosinophil counts were measured at 2.0 and 2.4 x 1,000/microliters in patients who received prior high-dose chemotherapy, compared with 3.2 and 5.1 x 1,000/microliters in those who did not.(ABSTRACT TRUNCATED AT 250 WORDS)

Anorexia↗
PubMed1989

A multicenter trial of interleukin-2 and low-dose cyclophosphamide in highly chemotherapy-resistant malignancies.

The anti-tumor activity of high-dose recombinant interleukin-2 (IL-2) has been demonstrated in several recent preclinical and clinical studies. In an attempt to study possible synergistic effects with low-dose cyclophosphamide (CYC), a phase II clinical trial was initiated in 32 patients, 18 with malignant melanoma (MM) and 14 with renal cell carcinoma (RCC). The recombinant IL-2 (Cetus Corp., Emeryville, Ca, U.S.A.) was given once daily at 3 x 10(6) U/m2, as a 30-min infusion for 14 days in cycle I and for five days twice in cycles II and III, respectively; if tolerated, the dose was escalated to a maximum of 6 x 10(6) U/m2/day; the cycles, separated by 1-week treatment-free intervals, were each preceded by a single i.v. bolus of CYC at 350 mg/m2. The most prominent side-effects encountered in this trial consisted of a capillary leak syndrome, myalgia and fever requiring dose reduction in half of the patients during the first cycle. Given the limit of tolerable toxicities in a standard care unit, the regimen employed achieved minor anti-tumor activity. No objective responses were achieved in patients with RCC and a 15% remission rate (PR + MR) was seen in melanoma patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

A phase-II trial of recombinant interleukin-2 and 5-FU chemotherapy in patients with metastatic colorectal carcinoma.

Seven patients with metastatic colorectal cancer have been treated with a regimen involving an 120-hour continuous infusion of rIL-2, 3 x 10(6) mu/m2. Entry restrictions included a Karnofsky index of greater than or equal to 80%, and a measurable lesion. One patient died of peritonitis secondary to bowel perforation at the site of the unresected tumour. One patient abandoned treatment following a pulmonary embolism during the first rIL-2 infusion. Other side effects included, pyrexia, rigors, nausea, hypotension, oliguria, weight gain, thrombocytopenia, neuropsychiatric symptoms and prerenal renal failure. Two patients have shown a greater than 50% regression in the size of their tumours and 3 have stable disease. The use of 'humanized' monoclonal antibodies together with mononuclear cells from patients receiving IL-2 infusions may provide a useful way of killing tumour cells which are resistant to lysis by LAK cells.

Aged↗
PubMed1989

A comparison of the toxicity and efficacy of cisplatin and carboplatin in advanced ovarian cancer. The Swons Gynaecological Cancer Group.

Eighty-eight patients with stage IIB-III epithelial ovarian cancer were randomised to receive first line single agent cisplatin (100 mg/m2) monthly or carboplatin (400 mg/m2) monthly for up to 5 cycles. Crossover to the opposite analogue occurred with progression or lack of response. All patients were premedicated with i.v. methylprednisolone (500 mg at 0 hours and 250 mg at 3 hours) and the first 20 patients in both groups received lorazepam and prochloperazine for nausea and vomiting. The median number of vomiting episodes per cycle with cisplatin was 16 and with carboplatin 2 (p less than 0.001). In the cisplatin arm 27/40 (67.5%) developed mild renal toxicity, 9/40 (22.5%) WHO grade I neurotoxicity and 18/40 (45%) evidence of ototoxicity at audiometry. To date we have seen no neuro- or ototoxicity with carboplatin and 1/40 (2.5%) have developed WHO grade I renal toxicity. Myelosuppression and anaemia was more common with carboplatin but only 1 episode of grade IV thrombocytopenia has been seen with first line carboplatin. The clinical response rate (CR+PR) for cisplatin was 19/40 and for carboplatin 27/40. Actuarial survival for cisplatin group at 24 months was 50% and for carboplatin group 58% with no significant difference. Carboplatin appears less toxic than cisplatin producing to date similar survival and response as a single agent.

Antiemetics↗
PubMed1989

Analysis of parameters for maximal in vitro proliferation and activation of lymphokine-activated killer cells (LAK).

In 15 patients (11 adults, 4 children) who received IL-2 and LAK cell therapy, we analyzed the different culture conditions which could either improve LAK cell activation and proliferation or which could simplify the procedure. Each parameter was assayed on a large scale and compared to standard culture conditions. Indomethacin had no effects, either positive or negative, on proliferation and activation of the cells. Culturing with 10% AB serum increased proliferation but did not modify total lytic activity compared to 2% AB serum. When cells were cultured in a medium with 2% autologous plasma obtained before any treatment, their proliferation was similar to that obtained in medium supplemented with 2% AB serum but the LAK activity was significantly higher. Autologous plasma obtained at day 8 of treatment (48 h after the first cycle of IL-2 and the day of the first cytapheresis) gave similar results to 2% AB serum. None of the 12 patients showed negative effects suggesting the presence of suppressive factors in the sera. Culturing with autologous plasma in clinical trials will lead to a 25% decrease in the total cost of culture and suppress the risk of viral contamination. Excess of granulocytes in the culture (greater than 30%), if the total nuclear cell concentration did not exceed 3 . 10(6) per ml, induced a better proliferation of mononuclear cells without modification of the activation. These results could be due to the liberation of factors by polynuclear cells, or to the loss during elimination of the granulocytes by the Ficoll separation of cells with similar density supporting LAK activity.

Adult↗
PubMed1989

Sequential administration of recombinant human interleukin-2 and dacarbazine in metastatic melanoma. A multicentre phase II study.

Twenty-four evaluable patients with metastatic melanoma have been entered in a multicentre Phase II study of two induction cycles of human recombinant interleukin-2 (rIL-2) 18 x 10(6) IU/m2/day continuous i.v. bolus on days 1-5 and days 12-17. Dacarbazine (DTIC) 850 mg/m2 i.v. bolus was given on day 26. The cycle was repeated at five weeks. Maintenance therapy was scheduled three weeks after the completion of the induction treatment, consisting of rIL-2 18 x 10(6) IU/m2/day for five days alternating with DTIC 850 mg/m2 i.v., every three weeks, for a total of 18 weeks. Median age was 44 years (range 23-80), and Karnofsky index was 100 (range 80-100). One patient had received prior chemotherapy with hydroxyurea and one patient had prior radiotherapy. Six patients responded (25%): two had complete responses (CR) and four had partial responses (PR). Stable disease (SD) was seen in five patients. Responses occurred in the following sites: liver 2/9 (22%), lung 3/14 (21%), skin 2/11 (18%), and lymph nodes 3/12 (25%). Duration of CR was 11+ and 13 months. PRs lasted 2, 5, 7, and 11+ months. Of note, time to progression in patients with SD was similar to that of responders: 4, 4, 11+, 11+, and 14+ months. Toxicity included fever, skin rash, fatigue, anorexia, and diarrhoea in most patients. Two patients had a weight gain of more than 10%. Hypotension requiring vasoactive agents or interruption of rIL-2 occurred in four patients, creatinine elevations WHO grade 1-2 in seven patients, and bilirubin elevations WHO grade 1-3 in six patients. One patient developed transient ventricular tachycardia. It appears that rIL-2 and DTIC in this schedule is feasible and effective, but not clearly superior to rIL-2 alone.

Adult↗
PubMed1989

Sequential dacarbazine chemotherapy followed by recombinant interleukin-2 in metastatic melanoma. A pilot multicentre phase I-II study.

Between April 1988 and August 1989, 30 melanoma patients were entered in a multicentre Phase II study of dacarbazine (DTIC) 850 mg/m2 i.v. bolus on day 1, and recombinant interleukin-2 (rIL-2) (Cetus) 18 x 10(6) IU/m2/day i.v. continuous infusion on days 4-9. Six treatment cycles were given: the first two at an interval of 13 days, and further cycles at intervals of 20 days. Twenty patients are currently evaluable for toxicity and 18 for response. Two of these patients presented with metastatic intraocular melanoma. Median age was 48 years (range 18-83), and median Karnofsky index was 100 (range 80-100). Four patients had received prior radiotherapy and one had received prior immunotherapy. Seventeen patients received two cycles of treatment and nine patients received three or more cycles. Four patients responded (22%): two complete remissions and two partial remissions. Stable disease was seen in six patients (33%). Responses occurred in the lung, skin, spleen and lymph nodes. Seventy-five percent of the patients received the full dose of rIL-2 during cycle 1, whilst only 2 out of 9 (22%) received the planned dose on the third cycle. Rebound lymphocytosis of 5.3 x 10(3)/L (range 1.2-18.1) occurred 24-48 h after rIL-2, but was not predictive for response. Currently, there is no evidence that pretreatment with DTIC impacts negatively on the rIL-2-stimulated lymphocyte proliferation. The toxicity profile of this treatment regimen did not differ significantly from that already described for similar regimens of rIL-2. However, in this interim analysis, there was a trend for a higher percentage of patients (25%) to experience severe weight gain (greater than 10%). This study shows that this treatment regimen is active in metastatic melanoma, with acceptable toxicity. Further research will focus on using other chemotherapeutic agents and/or other biological response modifiers (e.g. interferons, tumour necrosis factor) in combination with rIL-2.

Adolescent↗