Selected Kidney Cancer Abstracts – ASCO 2002

Phase I/II Study Of Thalidomide + Interleukin II (IL-2) For Patients With Metastatic Renal Cell Carcinoma

Robert J Amato, Suzanne Breheny, Elaine Tracy
Proc Am Soc Clin Oncol (ASCO Meeting Abstract) 2002;Abstract 759
Baylor College of Medicine, Houston, TX.

Thalidomide has anti-angiogenic and immunomodulatory effects, and has produced partial responses and prolonged stability in MRCC. We undertook a phase I/II study of thalidomide in combination with IL-2 to determine; safety and toxicity and whether we could increase the anti-tumor effect. Patients with a histologic diagnosis of confirmed renal cell carcinoma excluding sarcomatoid or collecting duct tumors who had radiographic demonstration of measurable tumor were eligible. Oral thalidomide was given daily, at bedtime. IL-2 was given by subcutaneous injection. See Table for the study design. A course was 6 weeks with the exception of course one being 7 weeks. Fifteen patients (10 males & 5 females) median age: 56 years (range 31-78 years) were enrolled in the phase I stage. Patients had Zubrod PS 0 (N=9) or 1 (N=6) at initiation of treatment. All patients had a nephrectomy. Eight patients had prior therapy. Time from diagnosis of metastatic disease ranged from 4 weeks to 19 months. The median number of metastatic sites were 2 (range 1-4). Three patients were entered on dose level 0, and six patients entered on dose level + 1 and +2, respectively. Ten of 15 patients have completed 12 weeks of therapy. Five partial responses have been observed. Two patients have had stable disease. Three patients have had progressive disease. The responses have been observed at each dose level. Treatment was generally well tolerated. Side effects attributed to thalidomide and IL-2 are sedation, constipation, skin rash, flu- like symptoms, fluid retention, hypotension, and deep venous thrombosis. On the basis of our phase I experience, we initiated the phase II stage utilizing dose level +1. The response rate with tolerable side effects observed in the phase I stage is encouraging. Further investigation of this combination as front line therapy is now accruing patients in the phase II stage.

Protocol Stage Dose Level Number of Patients

Thalidomide Dosage (Days 1-7 weeks 0,1-6)


Interleukin-2 Dose Levels (Days 1-5, weeks 1-4)
1 0 3 200mg 7mIU/m²
1 +1 3 400mg 7mIU/m²
1 +2 3 600mg 7mIU/m²
2   37 TBD 7mIU/m²

Phase I Trial Of Thalidomide And Interleukin-2 (IL-2) In Patients (Pts) With Metastatic Renal Cell Carcinoma (RCC)

Thomas Olencki, Robert Dreicer, Paul Elson, Laura Wood, Ronald M Bukowski
Proc Am Soc Clin Oncol (ASCO Meeting Abstract) 2002;Abstract 2430
Cleveland Clinic Foundation, Cleveland, OH.

Thalidomide and IL-2 may have different mechanisms of antitumor activity including immune mediated and anti-angiogenic.

Objective: A phase I study to investigate the toxicity, maximum tolerated dose (MTD) and in a preliminary manner the anti-tumor activity of thalidomide and IL-2 was initiated. Methods: Groups (Grps) of 3-6 pts with metastatic RCC were treated with IL-2 (MIU/m2/day SQ) at the following doses (week 1/week 2-6): Grps A-4.5/4.5; B-9.0/9.0; C-13.5/9.0; D18.0/9.0; E-18.0/9.0; F-18.0/9.0 and oral thalidomide daily for weeks 1-8 at 100 mg/day (Grps A-D), 200 mg/day (Grp E) and 400 mg/day (Grp F).

Results: Twenty pts have been entered and 19 are evaluable for toxicity. Median age is 62 years with ECOG performance status of (0/1) 40/60%. Nineteen, 95%, had a prior nephrectomy. 12/19 pts had prior systemic therapy (biologics 4-pts, biologics and XRT 6-pts, biochemo Tx 2-pts). Median number of cycles administered was 1 (range 1-4). Toxicity encountered included dyspnea in 1 pt and Gr II desquamation and puritis in 5 pts. Dose limiting toxicity was seen at dose level C and consisted of asymptomatic Gr III neutropenia in 3 pts that lasted 7-10 days. No evidence of thromboembolic activity was seen. A partial response was seen in 1/19 pts previously treated with an IL-2 based regimen.

Conclusions: The toxicity of combined IL-2 and thalidomide is moderate and the clinical significance of the observed neutropenia is uncertain. Further accrual at the MTD is planned. An intermediate dose of IL-2 and thalidomide 200 mg/ day is being considered.

A Randomized Double-Blind Placebo-Controlled Trial Of Bevacizumab (Anti-VEGF Antibody) Demonstrating A Prolongation In Time To Progression In Patients With Metastatic Renal Cancer

James C Yang, Leah Haworth, Seth M Steinberg, Steven A Rosenberg, William Novotny
Proc Am Soc Clin Oncol (ASCO Meeting Abstract) 2002;Abstract 15
National Cancer Inst NIH, Bethesda, MD; Genentech Inc, San Francisco, CA.

Background: Mutations in the VHL tumor-suppressor gene which cause the majority of clear cell renal carcinomas (RCC) also lead to deregulation and oversecretion of vascular endothelial growth factor (VEGF) by this highly vascular tumor. A clinical trial to evaluate the activity of a neutralizing antibody to VEGF was performed in patients with metastatic RCC. Methods: A prospective 3-arm, double-blind trial comparing placebo (P), 3 mg/kg (LD) and 10 mg/kg (HD) antibody given every two weeks was performed with time-to- progression and response rate as primary endpoints. Crossover from placebo was allowed and survival was a secondary endpoint.

Results: Arms were well balanced for prognostic factors. Toxicity at both doses of antibody was minimal with hypertension and asymptomatic proteinuria the most prominent. After 110 patients were randomized (38 P, 35 LD and 37 HD), interim analysis showed a highly significant prolongation of time- to-progression of HD antibody vs. P (hazards ratio=2.3, p=0.001) satisfying early stopping criteria. The difference between LD and P was of borderline significance. There were only 3 partial responses, all to HD antibody (RR= 8%). At last analysis, 58% of patients were alive, so survival data is still immature.

Conclusions: VEGF appears to be important in the growth of metastatic RCC. 10 mg/kg of bevacizumab significantly prolongs time-to-progression in patients with metastatic renal carcinoma with minimal toxicity, but tumor regression is rarely seen. This randomized prospective demonstration of biological activity of an antiangiogenic agent in patients with metastatic cancer has implications for the design of trials for similar agents and in future combination therapies.

Multicenter Phase-III Trial To Compare Radical Nephrectomy Plus Adjuvant Autologous Tumor Cell-Lysate Vaccine Versus Radical Nephrectomy Without Adjuvant Treatment For Renal Cell Carcinoma Stages PT2-3bpN0-3M0: A 3- Year Analysis.

Christian Doehn, Axel Richter, Walter Lehmacher, Dieter Jocham, Dept of Urology, University of Lübeck Medical School, Lübeck, Germany; Dept of Urology, University of Lübeck Medical School, Leipzig, Germany; Institute for Medical Statistics, University of Cologne Medical School, Cologne, Germany.
Proc Am Soc Clin Oncol (ASCO Meeting Abstract) 2002;Abstract 717

Purpose: Radical nephrectomy for non-metastasized renal cell carcinoma (RCC) is associated with tumor progression in a significant proportion of patients. Nevertheless, no effective adjuvant treatment after radical nephrectomy has been established. We compared radical nephrectomy plus adjuvant autologous tumor cell-lysate vaccine versus radical nephrectomy without adjuvant treatment for renal cell carcinoma.

Patients and Methods: Between January 1997 and August 1998 a total of 558 patients with RCC stages pT2-3bpN0-3M0 (TNM-classification, UICC 1993) were enrolled at 55 different centers in Germany. Prior to radical nephrectomy all patients were centrally randomized to receive adjuvant autologous tumor cell-lysate vaccine (6 applications at 4-weeks intervals after radical nephrectomy) or no adjuvant treatment (control group) after radical nephrectomy. Following the inclusion criteria 365 patients (131 women and 234 men, median age 59.3 years) were evaluable for the 3-year progression-free survival. There were 240 patients with stage pT2pN0M0 and 89 patients with stage pT3pN0M0. The remaining 35 patients had positive lymph nodes. The trial was performed according to ICH-GCP guidelines.

Results: The 3-year progression-free survival rates (according to Kaplan-Meier) for all tumor stages were 84,7% (vaccine group) and 80.9% (control group), respectively. Patients with RCC stage pT3pN0M0 in the vaccine group demonstrated an advantage (74.4% in the vaccine group vs. 65.9% in the control group). For RCC stage pT2pN0M0 the 3-year progression-free survival rate in the vaccine group was 89.7% compared to 85.7% in the control group. Follow-up of all patients enrolled in this trial is ongoing.

Conclusions: This is the first randomized study indicating a benefit from an adjuvant vaccination in patients with non-metastasized RCC after radical nephrectomy. The advantage in terms of progression-free survival was more pronounced in patients with T3-tumors than in T2-tumors.

A Prospective Study Of Salvage Surgery And Additional Systemic Therapy Following Initial Response In Metastatic Renal Cell Carcinoma (RCC)

Vasileios J Assikis, Christopher Logothetis, Peter Thall, Joe Putnam Jr., Shi-Ming Tu, David Swanson, Xuemei Wang, Christos Papandreou, Danai Daliani
Proc Am Soc Clin Oncol (ASCO Meeting Abstract) 2002;Abstract 756
M.D. Anderson Cancer Center, Houston, TX.

OBJECTIVE: To prospectively determine the overall survival of patients with metastatic RCC with clinical response or stable disease to initial systemic therapy who underwent salvage surgery with curative intent and additional systemic treatment.

PATIENTS: 38 consecutive patients were enrolled from 1992-1999. Median age was 55 (36-71); performance status of 0-1. 37/38 underwent nephrectomy and 1/38 embolization of the affected kidney. 17/38 had metastatic disease on presentation. Histology was clear cell carcinoma in 74%. Incidence of metastatic sites: lung (55%), lymph nodes (32%), renal bed (16%), bone (10%) and other (10%). Initial systemic treatment included biologic agents (interferon-a (IFN-a), interleukin-2 (IL-2), or tumor vaccine) with or without chemotherapy (5-fluorouracil (5-FU), FUDR) and was administered for a median of 5 months (3-15). Almost half of all patients (45%) received intravenous or subcutaneous IL-2. Response to initial therapy was: stable disease (79%), partial response (PR) (18%), complete response (CR) (3%). All patients underwent salvage metastasectomy with curative intent followed by additional systemic therapy (in most cases the initial regimen or IFN-a plus 5-FU) for a median of 4 months.

RESULTS: 29/38 (76%) were rendered disease-free after salvage surgery. 34/38 received additional systemic therapy after surgery. Overall median survival was 4.7 years. Median time to progression was 1.8 years (95% C.I. 1.0-4.4). Interestingly, lymph node metastasis was a poor prognostic factor (hazard ratio: 2.66, p=0.04). Median survival was 5.6 years for those rendered disease-free with salvage surgery vs. 1.4 years for those with residual RCC (p=0.0005).

CONCLUSION: Salvage surgery in metastatic RCC is feasible. Complete resection of metastases in select patients with stable/responding disease to initial systemic treatment is associated with prolonged survival. The role of adjuvant systemic therapy following successful salvage metastasectomy should be studied in a prospective controlled trial.

High-Dose Toremifene (HDT) For The Treatment Of Locally Advanced And Metastatic Renal Cell Carcinoma

Michael M Gershanovich, Andrey I Gorelov, Alajos Hajba, N.N. Petrov Research Institute of Oncology, St. Petersburg, Russia; State University Hospital, Dept of Medicine, St. Petersburg, Russia; Orion Pharma, Oncology Clinical Research, Turku, Finland.
Proc Am Soc Clin Oncol (ASCO Meeting Abstract) 2002;Abstract 757

Advanced or metastatic renal-cell carcinoma is considered to be resistant to hormonal- or cytotoxic treatment or their combinations. The only FDA approved treatment in this condition is high-dose interleukin-2, which results in 10-15% objective response rate and associated with high frequency of severe toxicity. Toremifene (Fareston®) is an antiestrogen of triphenylethylene structure which today is used in the treatment of postmenopausal breast cancer at a daily dose of 40 or 60 mg/day. Preclinical findings indicate a dose dependently extending efficacy profile. Application of HDT in human clinical setting was not associated with increased rate or changed profile of adverse events. The purpose of the present prospective study was to evaluate the efficacy and safety of HDT in the treatment of locally advanced and metastatic renal cell carcinoma. Alltogether 19 (9 male, 10 female, age 27-91 years) patients, with liver- (6), lung- (6), abdominal lymph node- (3), skeletal- (2) and soft tissue- (7) metastasis or inoperable primary tumor (3) were enrolled to receive toremifene 360 mg daily, of them 1 was lost to follow-up. Of the 18 evaluable patients 1 had CR (5,5%, duration 10+m.), 4 PR (22,2%, duration 7+, 4, 10 and 14m.) and 7 NC (38,8%, duration ranged 4-30+m.), indicating a total clinical benefit of 66,3%. Seven patients progressed. Total or partial pain control was associated in 70% of the patients independent in the treatment outcomes. No treatment related adverse events were found. In our earlier experiment toremifene 300 mg daily exerted a total clinical benefit (CR; PR and NC) of 44,4%. Based on our earlier and present findings we conclude that 1. HDT is an effective and safe treatment for the locally advanced or metastatic renal-cell carcinoma, 2. Higher dose of toremifene seems to exert better treatment outcomes, without increasing the rate or severity of adverse events, 3. Pain control that is experienced by most of the patients during HDT treatment means improved quality of life compared to other available treatment options for this condition.