A phase II study of FolateImmune (EC90 with GP1–0100 adjuvant followed by EC17) with low dose cytokines interleukin-2 (IL-2) and interferon-α (IFN-α) in patients with refractory or metastatic cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 13516-13516 ◽  
Author(s):  
R. Messmann ◽  
R. Amato ◽  
J. Hernandez-McClain ◽  
B. Conley ◽  
H. Rogers ◽  
...  
Keyword(s):  
Immune Response ◽  
Phase Ii ◽  
Low Dose ◽  
Metastatic Cancer ◽  
Cell Cancer ◽  
Interleukin 2 ◽  
Phase Ii Trials ◽  
Minor Response ◽  
Pathologic Classification ◽  
Study Laboratory

13516 Background: FolateImmune is a folate-receptor (FR)-targeted immunotherapy that induces an immune response against tumor cells by marking them with a folate-hapten conjugate. The conjugate is specifically designed to target FR, which is over-expressed in a variety of cancers. FolateImmune therapy is comprised of a vaccine fluorescein conjugate (EC90), an adjuvant (GP-0100), and a folate-hapten conjugate (EC17). Patients (pts) receive a series of subcutaneous (SQ) injections of EC90 vaccine to stimulate the production of antibodies to the fluorescein-hapten, followed by SQ injections of EC17, which forms a molecular bridge between the tumor cell and the endogenous circulating anti-fluorescein IgG antibody. This is thought to initiate an Fc-mediated immune response leading to antibody-dependent cellular cytotoxicity and/or phagocytosis. IL-2 and IFN are utilized at low doses (7 MIU and 3 MIU, respectively) to further promote an immune response. The Phase Ib objective is to determine the safety of EC90 vaccine/EC17 folate-targeted therapy in combination with IL-2 and IFN. The previous phase I trial explored the safety of FolateImmune without cytokines. Methods: This phase 1b safety study treated eligible patients with FolateImmune therapy at dose levels of 1.2 mg EC90 and EC17 of 0.3 mg/kg. Results: As of Jan 2, 2007, all patients have tolerated therapy without significant toxicity. Grade 1–2 toxicity included: chills, fever, and nausea. One patient has had a minor response and continues on study. Laboratory studies revealed decline in circulating FR+ cells. Of 6 pts enrolled, 5 had a pathologic classification of renal cell cancer (RCC). Conclusion: Preliminary data suggest that FolateImmune therapy, with the addition of low dose cytokines, may be administered in a safe and well-tolerated manner. Phase II trials are planned for RCC. No significant financial relationships to disclose.

Metastatic renal cell cancer treated with low-dose interleukin-2. A phase-II multicentre study

1989 ◽  
Vol 16 ◽  
pp. 111-113 ◽  
Author(s):  
G. Stoter ◽  
S.D. Fosså ◽  
C. Rugarli ◽  
M. Symann ◽  
C. Jasmin ◽  
...  
Keyword(s):  
Multicentre Study ◽  
Phase Ii ◽  
Renal Cell Cancer ◽  
Renal Cell ◽  
Low Dose ◽  
Cell Cancer ◽  
Interleukin 2 ◽  
Metastatic Renal Cell Cancer

Phase II clinical trial of low-dose interleukin-2, interferon-alpha, and low-dose tegafur uracil therapy for advanced renal cell cancer.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 508-508
Author(s):  
Tomoyuki Kato ◽  
Masatsugu Iwamura ◽  
Tetsuo Fujita ◽  
Seiichi Saito ◽  
Yoshinori Ohshiro ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Interferon Alpha ◽  
Phase Ii ◽  
Renal Cell Cancer ◽  
Pulmonary Metastasis ◽  
Renal Cell ◽  
Low Dose ◽  
Cell Cancer ◽  
Interleukin 2 ◽  
Ifn Alpha

508 Background: The objective of this trial was to evaluate the efficacy and safety of immunochemotherapy with very low-dose interleukin-2, interferon-alpha and tegafur uracil (IAT therapy) in treatment naïve metastatic renal cell carcinoma (RCC) patients with pulmonary metastasis only. Methods: Previously untreated metastatic renal cell cancer patients only with pulmonary metastasis were enrolled in this multicenter, open-label, single arm, phase II trial. Eligibility criteria included ECOG performance status (PS) 0-2, low or intermediate risk per MSKCC score, and adequate organ function. The primary endpoint was the overall response rate (ORR) per RECIST v1.1. Secondary endpoints were time to progression (TTP), response duration, overall survival (OS), ECOGPS and safety. Safety was assessed by CTCAE, v4.0. Low dose (0.7-2.1 MIU/ day) IL-2 was administered intravenously in the first five days of the first and third week. IFN-alpha (500 MIU/day) was administered 3 times per week in week 2. From 4th to 7th weeks, patients received IFN- alpha 3 times per week and 100 mg tegafur uracil t.i.d. Results: Twenty-eight eligible patients were enrolled from Apr 2009 through Dec 2013. Twenty-one patients were evaluable for ORR. Three patients had partial response (PR) 11 stable disease (SD), and 7 progressive disease (PD). ORR was 14.4% and median duration of PR was 18.0 months. TTP and OS were not reached to median and 3-year OS rate was 76.3%. Twenty-seven patients (96.4%) had an ECOGPS of 0 and 1 (3.6%) had PS of 1. Three patients experienced exacerbation in PS (PS 0 to 1). The most common adverse events (AEs) were elevation of ALT (35.7%) and fever (32.1%). AEs grade 3 included rash (14.3%), depression (3.2%), syncope (3.2%), fever (3.2%), elevation of ALT (3.2%). Four patients discontinued therapy at the time of ORR analysis due to AEs (3 rash, 1 depression). Conclusions: IAT therapy for RCC patients with only pulmonary metastasis is safe and appears to have clinical benefit as reflected by ORR rate and long OS. Clinical trial information: 00002222.

Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: analysis of toxicity and management guidelines.

1989 ◽  
Vol 7 (4) ◽  
pp. 486-498 ◽  
Author(s):  
K A Margolin ◽  
A A Rayner ◽  
M J Hawkins ◽  
M B Atkins ◽  
J P Dutcher ◽  
...  
Keyword(s):  
Phase Ii ◽  
Performance Status ◽  
Cell Cancer ◽  
Killer Cell ◽  
Interleukin 2 ◽  
Ventilatory Support ◽  
High Dose ◽  
Phase Ii Trials ◽  
Organ Function ◽  
Life Threatening

The National Cancer Institute (NCI) Extramural IL2/LAK Working Group treated 93 patients with 114 cycles of high-dose intravenous (IV) interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells in three phase II trials. Thirty-six patients had metastatic melanoma, 35 had metastatic renal cell cancer, and 22 had colorectal cancer. All patients had a Karnofsky performance status greater than or equal to 80% and normal laboratory tests and organ function, and had received no more than one prior form of immunotherapy or chemotherapy. Objective responders were eligible to receive up to two additional courses of therapy at 12-week intervals. The most frequent toxicities were a capillary leak syndrome resulting in marked extravascular fluid shifts, and hypotension requiring treatment with large volumes of IV fluids and vasopressor agents. Laboratory and clinical evidence of hepatic and renal dysfunction were virtually universal. Intensive care-level support was routinely provided and the toxicity observations confirmed the need for this level of care. The life-threatening toxicities were cardiac and pulmonary. Five of the 27 patients who experienced significant respiratory compromise required intubation and mechanical ventilatory support. Twenty patients developed cardiac arrhythmias, the majority of which were supraventricular. There was a single episode of ventricular tachycardia requiring cardioversion. Four patients had transient cardiac ischemia, and an additional four had myocardial infarctions, one of which was fatal. With these exceptions, all toxicities were rapidly reversible. The occurrence of only a single therapy-related death and a very low incidence of other irreversible or life-threatening events is comparable to the level of toxicities often observed in other phase II trials. Although the intensity of this regimen limits this approach to a subset of cancer patients with excellent performance status and adequate organ function, because of the frequency and apparent durability of complete responses, this treatment warrants further investigation.

scholarly journals Three Phase II Cytokine Working Group Trials of gp100 (210M) Peptide Plus High-Dose Interleukin-2 in Patients With HLA-A2–Positive Advanced Melanoma

2008 ◽  
Vol 26 (14) ◽  
pp. 2292-2298 ◽  
Author(s):  
Jeffrey A. Sosman ◽  
Carole Carrillo ◽  
Walter J. Urba ◽  
Lawrence Flaherty ◽  
Michael B. Atkins ◽  
...  
Keyword(s):  
Phase Ii ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
Advanced Melanoma ◽  
Phase Iii ◽  
Clinical Activity ◽  
High Dose ◽  
Phase Ii Trials ◽  
Cell Immunity ◽  
Three Phase

Purpose High-dose interleukin-2 (IL-2) induces responses in 15% to 20% of patients with advanced melanoma; 5% to 8% are durable complete responses (CRs). The HLA-A2–restricted, modified gp100 peptide (210M) induces T-cell immunity in vivo and has little antitumor activity but, combined with high-dose IL-2, reportedly has a 42% (13 of 31 patients) response rate (RR). We evaluated 210M with one of three different IL-2 schedules to determine whether a basis exists for a phase III trial. Patients and Methods In three separate phase II trials, patients with melanoma received 210M subcutaneously during weeks 1, 4, 7, and 10 and standard high-dose IL-2 during weeks 1 and 3 (trial 1), weeks 7 and 9 (trial 2), or weeks 1, 4, 7, and 10 (trial 3). Immune assays were performed on peripheral-blood mononuclear cells collected before and after treatment. Results From 1998 to 2003, 131 patients with HLA-A2–positive were enrolled. With 60-month median follow-up time, the overall RR for 121 assessable patients was 16.5% (95% CI, 10% to 26%); the RRs were 23.8% in trial 1 (42 patients), 12.5% in trial 2 (40 patients), and 12.8% in trial 3 (39 patients). There were 11 CRs (9%) and nine partial responses (7%), with 11 patients (9%) progression free at ≥ 30 months. Immune studies including assays of CD3-ζ expression and numbers of CD4+/CD25+/FoxP3+ regulatory T cells, CD15+/CD11b+/CD14– immature myeloid-derived cells, and CD8+gp100 tetramer-positive cells in the blood did not correlate with clinical benefit. Conclusion The results again demonstrate efficacy of high-dose IL-2 in advanced melanoma but did not demonstrate the promising clinical activity reported with vaccine and high-dose IL-2 in any of three phase II trials.

A multicenter phase II study of thalidomide in combination with interleukin-2 (IL-2) in patients with previously untreated metastatic renal cell carcinoma (MRCC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14636-14636 ◽  
Author(s):  
D. Farray ◽  
J. I. Clark ◽  
T. Kuzel ◽  
J. P. Dutcher
Keyword(s):  
Phase Ii ◽  
Low Dose ◽  
Group Performance ◽  
Clear Cell ◽  
Phase Ii Study ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Interleukin 2 ◽  
Open Label ◽  
Anti Tumor Activity

14636 Background: Thalidomide, a drug with immune modulating and anti-angiogenic properties has shown activity in relapsed/refractory MRCC; furthermore, early phase I data of oral thalidomide with subcutaneous low-dose IL-2 showed the combination to be safe. The potential anti-tumor activity of this combination formed the basis of this study. Methods: The aim of this multi-center, open label, phase II study was to determine the efficacy and safety of thalidomide and IL-2 given in combination. Patients (pts) with untreated clear cell MRCC with measurable disease and previous nephrectomy were eligible. Two 6-week cycles of thalidomide and IL-2 were planned. Each cycle consisted of thalidomide started at 200 mg orally daily and titrated to 400 mg daily on the 4th day for 6 weeks; IL-2 was started one week post initiation of thalidomide at a dose of 7mIU/m2 subcutaneously days 1–5 for 4 weeks, followed by 2 weeks off therapy. Therapy was to be continued until progression, if there was at least stable disease (SD). Planned accrual was 53 patients. Results: 11 pts were enrolled. The trial was terminated early due to lack of responses. Median age was 57 years (51–66). All pts had an Eastern Cooperative Oncology Group performance status of 2 or better. The only grade 3 toxicities were fatigue (3 pts), neuropathy (1 pt), anorexia (1 pt), dyspnea (1 pt), edema (1 pt); these required dose reductions as per protocol. There were no objective responses: 3 pts had SD, 8 pts had progressive disease (PD). The 3 pts with SD completed 4, 4, and 6 cycles of therapy respectively; of the 8 pts with PD, 3 completed two cycles, and 5 completed one cycle of therapy. Conclusions: The combination of thalidomide and low-dose IL-2 was well tolerated, but in this trial did not show anti-tumor activity in patients with clear cell MRCC. We thank Celgene for support of this trial. No significant financial relationships to disclose.

A phase II trial of low-dose interleukin-2 (IL-2) and bevacizumab in patients with metastatic renal cell carcinoma (mRCC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5103-5103 ◽  
Author(s):  
J. A. Garcia ◽  
B. I. Rini ◽  
T. Mekhail ◽  
P. Triozzi ◽  
P. Elson ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase Ii ◽  
Low Dose ◽  
Overall Response Rate ◽  
Phase Ii Trial ◽  
Interleukin 2 ◽  
Organ Function ◽  
Normal Organ ◽  
Immune Correlates ◽  
Binding Antibody

5103 Background: Interleukin-2 and bevacizumab, a VEGF ligand-binding antibody, have each demonstrated antitumor activity in mRCC. Increased VEGF levels can lead to immunosuppression and resistance to immunotherapy through inhibition of dendritic cell (DC) differentiation and increase in immunosuppressive regulatory T cells (Tregs). To further evaluate the clinical and immunomodulatory effect of low-dose IL-2 and bevacizumab in mRCC, a phase II trial was conducted. Methods: Previously untreated good and intermediate risk mRCC pts received 8-week cycles of IL-2 (250,000 U/kg/d SC D1–5 during week 1 and 125,000 U/kg/d SC D1–5 during weeks 2–6, followed by a 2 week break). Bevacizumab 10mg/kg was administered IV every 2 weeks starting on day -14. Eligibility included RECIST-defined measurable disease, clear cell histology, normal organ function, and prior nephrectomy. A Simon 2 stage phase II design was employed to test the hypothesis of a 40% improvement in the 3-month PFS vs. historical IL-2-treated controls. Overall response rate (ORR) and toxicity were recorded. Exploratory endpoints included activation of circulating DC’s, Tregs and VEGF levels. Results: To date 16 of a planned 35 pts are enrolled. Median age is 59 years (range, 44–67); Eight patients have >1 site of metastasis; median treatment duration is 8 weeks (8–32+). Among 11 pts evaluable for response, 1 PR and 3 SD lasting >3 months have been observed. All pts with SD have demonstrated some degree of tumor shrinkage. Seven pts have discontinued therapy (5 PD, 2 withdrew consent). Most common treatment-related toxicity included fatigue, nausea, diarrhea, and fever. When comparing immune correlates at day 56 of therapy vs. baseline, all pts had an increase in the number of Tregs (median increase 1.65, range; 0.76–10.4; p= 0.008). Similarly, all pts had a decline in VEGF levels (median decline 164.38 pg/ml, range; 2.20–393.04 pg/ml; p= 0.008). No differences in DC activation have been observed. Conclusions: The combination of LD IL-2 and bevacizumab produces antitumor activity and moderate toxicity. Preliminary correlative data demonstrates inhibition of VEGF and increase in Tregs without effect on DC activation. No significant financial relationships to disclose.

Adjuvant low-dose interleukin-2 (IL2) plus interferone-alpha (IFN) in operable renal cell cancer (RCC). A phase III, randomized, multicenter, independent trial of the Italian Oncology Group for Clinical Research (GOIRC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. LBA5028-LBA5028 ◽  
Author(s):  
R. Passalacqua ◽  
C. Buzio ◽  
S. Buti ◽  
R. Labianca ◽  
C. Porta ◽  
...  
Keyword(s):  
Low Dose ◽  
Cell Cancer ◽  
Interleukin 2 ◽  
Disease Free Survival ◽  
Tumor Grade ◽  
Phase Iii ◽  
Who Grade ◽  
Free Survival ◽  
Repeated Doses

LBA5028 Background: For pts with non-metastatic RCC, no standard adjuvant treatment exists. Immunotherapy (IT) using IFN and/or IL2 is effective in metastatic disease setting. Low and chronically repeated doses of IL2 plus IFN induce a persistent stimulation of the immune system with no relevant toxicity. Methods: From July1994 to March 2006, surgically treated RCC pts were randomized to the following arms: A) low-dose IT; B) control arm. IT consisted of a 4-week cycle of s.c. IL2 (5 days/wk, 1 million UI/sqm bid d 1,2 and 1 million UI/sqm × 1 d 3,4,5) + IFN (1,8 million UI/sqm d 3,5 of each week). Cycles were repeated every 4 months for the first 2 years and every 6 months for the remaining 3 years. Each patient received 12 cycles in 5 years. Inclusion criteria were as follows: histological diagnosis of RCC, age <75 yrs, radical or partial nephrectomy within the past 3 months, pT1 (diameter of T > 2,5 cm), T2, T3 a-b-c; pN0-pN3, M0; good cardiac and renal function and no autoimmune disease. Based on a planned sample size of 320 pts, the trial was designed to have a 80% power to detect a 15% improvement in 5-year survival. Results: A total of 310 pts were randomized: 157 on arm A, 153 on arm B. Pts characteristics were well balanced between the two arms. At a median follow-up of 52 months, 77 pts relapsed: 35 in arm A and 42 in arm B. In the first 5 years of observation, disease free survival (DFS) curves were similar in the two arms, but diverged thereafter. DFS at 5 and 10 years was 0.73 and 0.73 in arm A vs 0.73 and 0.60 in arm B with an estimated Hazard Ratio (HR) of 0.84 (95% CI: 0.54–1.33 p=0.47). Efficacy of IT was more evident in patients with good PS (HR 0.78; 0.47–1.30 p=0.35); age<60 yrs (HR 0.61; 0.31–1.19 p=0.15), and low tumor grade (HR 0.70; 0.38–1.27 p=0.24). As for overall survival, 59 deaths were observed with no differences between the two arms. Toxicity was mild and limited to WHO grade 1 or 2 in the majority of cases. Conclusions: Low-dose adjuvant IL2+IFN is feasible in RCC and seems to reduce the risk of recurrence after 5 years from diagnosis. Follow-up update is still ongoing. No significant financial relationships to disclose.

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