Action to Cure Kidney Cancer

Interleukin-21 is a protein that has a regulatory effect on the body's immune system by activating T-cells and natural killer (NK) cells, which normally target cancer cells for destruction. It is similar to Interleukin-2 in this respect, however, IL-2 induces proliferation of regulatory T (T-reg) cells, which are immune suppressor cells that are necessary to keep the immune system from attacking healthy body tissue but may have a dampening effect on the ability of IL-2 to fight tumors. IL-21 does not enhance proliferation of T-reg cells.

There are three recent IL-21 trials of interest:

1. Phase 1, dose-escalation study of subcutaneous Interleukin-21 in Stage IV rcc and melanoma patients run by Henrik Schmidt at the Aarhus University Hospital in Denmark. This trial was reported on in a poster presentation at ASCO 2008.
   
2. Phase 1, multi-center trial using intravenous IL-21 for rcc and melanoma patients, reported in the Journal of Clinical Oncology in April 2008 by John Thompson of the University of Washington.
   
3. Phase 1/2, multi-center trial in rcc patients using intravenous IL-21 in combination with sorafenib (Nexavar) originally reported on by Shailender Bhatia, a colleague of John Thompson's, at the AACR-NCI-EORTC conference October 2007 and updated by Dr. Bhatia in an abstract at ASCO 2008.

Phase 1 Subcutaneous IL-21 Study at Aarhus University

The results of this trial were presented in a poster session at ASCO 2008. Treatments were scheduled for 3 times per week for 8 weeks with possible continuation depending on response. The primary objective of this dose-escalated study was to determine maximum tolerated dose. Dosing levels were set at 3, 10, 30, 100, 200 and 300 μg/kg (microgram per kilogram).

23 patients were treated, 12 with melanoma and 11 with rcc. 16 of the patients had previous therapy. The investigators categorized the rcc patients according to the Memorial Sloan-Kettering risk categories with 6 having favorable risk and 5 having intermediate.

Adverse Events

Most adverse events were grade 1/2. Dose limiting toxicities began to appear at the maximum dose level, i.e. 300 μg/kg, in two of seven patients. The most frequent adverse events were headache, fatigue, injection site reactions, myalgia (muscle pain), and fever.

Response

To date, only 14 patients of the 23 are evaluable for response and of those 3 have had responses: one complete response in melanoma for an 8-month duration and two partial responses in kidney cancer (one with an abdominal mass and the other with lung and mediastinal lymph node mets). The abdominal mass patient had had previous IL-2 and sorafenib (Nexavar) treatments with no response. After 32 weeks of treatment and tumor shrinkage, the remaining tumor was resected. These two rcc patients were treated at a dosage of 200 μg/kg, one level below the maximum. There were no observed responses in the other 11 patients.

Discussion

The results of this trial are not mature enough to evaluate, however, the early response data are encouraging especially given the fact that 70% of the patients failed prior treatment(s). Given the early favorable results of subcutaneous IL-21, one would expect a continuation Phase 2 trial to test the efficacy of the drug. However, Henrik Schmidt told ACKC that Novo Nordisk, the European distributor of IL-21 (the drug is produced by an American biotech company called ZymoGenetics), is about to sell its distribution license for IL-21. Therefore, future testing of the drug in Europe, at least in the near term, is uncertain.

Phase 1 Multi-Center Trial in RCC and Melanoma using Intravenous IL-21

John Thompson of the University of Washington presented the results, in an article in the Journal of Clinical Oncology (JCO Apr 20 2008: 2034-2039) of a Phase 1, multi-center trial of IL-21 in rcc and melanoma. The primary endpoints of the trial, i.e. the objectives, were to determine the maximum tolerated dose (MTD) and safety of the drug.

There were 43 patients, 19 renal cell and 24 melanoma. Of the 43 patients, 15 were accrued during the dose escalation phase (6 rcc and 9 melanoma) and 28 during expansion of the trial after the MTD was determined (13 rcc and 15 melanoma). Of the 19 rcc patients, 15 had a prior nephrectomy and 14 had prior therapy, 8 of them IL-2. The rcc patients were predominantly clear cell.

Methodology

The treatment methodology consisted of two 5-day cycles of daily intravenous infusions of IL-21 at days 1-5 and 15-19 with possible repetition of treatment depending on disease response, i.e. SD (stable disease) or better; treatment was done on an outpatient basis.

Adverse Events

The MTD was determined to be 30 μg/kg (micrograms per kilogram) at which 28 patients from cohort expansion and 6 patients from dose escalation group were treated. All 34 of these patients, who participated in the 1^st treatment course, i.e. the 10 days of IL-21 at the MTD, exhibited at least one adverse event. The maximum severity of adverse events was grade 1 for 9 pts (26%), grade 2 for 21 pts (62%), and grade 3 for 4 pts (12%). The most common events were fever, fatigue, chills, and headache, all limited to grades 1/2. Most laboratory abnormalities were also grade 1/2. Lymphopenia (low levels of white blood cells), was observed in 88% of patients with 9% having grade 4. For the most part, there was no increased toxicity in the patients who underwent further courses of treatment.

Responses

For the 24 patients with melanoma and the 19 patients with rcc, the response was as follows.

The CR melanoma patient was initially a partial responder for 5 months, then a complete responder for 3 months, then progressed.

All the rcc partial responders eventually progressed: one after 5 months, the second after 10 months, the third after 12 months, and the final one after 18½ months.

Discussion

This was a Phase 1 trial whose objective was to determine the maximum tolerated dose and safety of IL-21. The investigators determined the MTD to be 30 μg/kg, which caused tolerable toxicities, but they didn't push the dosage beyond that to see if a higher concentration could be tolerated. At 30 μg/kg, there were anti-tumor responses but no durable ones. Dr. Thompson compared IL-21 to IL-2 treatment, which has higher toxicity but longer durable responses. Testing for the efficacy and durability of responses of IL-21 will have to await a Phase 2 trial. Dr. Thompson also noted that for the 14 rcc patients who had prior therapy, it is possible that the prior therapy had an impact on the response rate to IL-21.

There don't seem to be any current plans to continue testing of IL-21 as a monotherapy in rcc. The University of Washington is proceeding with testing IL-21 in combination with sorafenib (Nexavar). See the next report for an update on this combination.

Phase 1/2, Multi-center Trial in rcc Patients Using Intravenous IL-21 in Combination with Sorafenib (Nexavar)

This trial was originally reported by Shailender Bhatia of the University of Washington at the AACR-NCI-EORTC International Conference in October 2007 in San Francisco and then updated in an abstract at ASCO 2008.

There were initially 13 patients in Phase 1, categorized as favorable (9) and intermediate (4) using the Memorial Sloan-Kettering risk categories. Seven of the patients, or 54%, had had prior treatments.

Methodology

The design of this study was to initiate a Phase 1 dose-escalation trial, open to 1^st and 2^nd line patients, combining IL-21 with sorafenib to determine the maximum tolerated dose (MTD) and safety of IL-21. At that point, a Phase 2 trial would be initiated at the MTD to test the efficacy in an additional 30 patients (overall response rate and progression-free survival) of IL-21 in 2^nd and 3^rd line patients who had failed previous therapy. The dose escalation trial would test 10-30-50 μg/kg doses of IL-21.

For Phase 1, the treatment was given in 6-week cycles with IL-21 infusions on days 1-5 and 15-19, plus sorafenib on a daily basis with a CT scan at end of each cycle and continuation to next cycle based on stable disease (SD) or better. The dosages were: sorafenib 400 mg twice a day (standard for this drug as a mono-therapy), and, as mentioned, for IL-21, dose escalation 10-30-50 μg/kg.

At the time of the ASCO abstract, 19 patients had been enrolled, 3 had withdrawn because of toxicity, 2 had withdrawn because of the dosing errors, leaving 14 patients to be treated in the dose-escalation phase. However, 2 of them exhibited dose limiting toxicities at 50 μg/kg, so another dose level was opened at 40 μg/kg, and 3 new patients are on that protocol, making a total of 17 patients.

Sorafenib as a 2^nd line treatment has median 5.5 mos pfs and 2% PR per Escudier NEJM 2007 356(2) 125-134.

Adverse Events

Most adverse events were grade 1/2. The prominent grade 3 adverse events and the major grade 3/4 lab abnormalities were as follows.

Three of the patients didn't complete the first course of treatment due to toxicity, specifically, a diffuse rash accompanied by hand-foot syndrome in all three patients. In addition, as already mentioned, there were two dose limiting toxicities in two of four patients at the 50 μg/kg dose level.

Responses

As of May 2008, 10 patients were evaluable for tumor response. By investigator evaluation, all 10 patients had tumor shrinkage, after the first treatment cycle, and all 10 received additional cycles of treatment. Two patients had confirmed partial responses (investigator evaluation). Two patients had withdrawn because of progressive disease, and one had withdrawn after 4 treatment courses with stable disease (response had leveled off).11 patients continue on study.

NB: The response data and adverse events statistics for this Phase 1 trial were assembled from a variety of sources: a poster presentation, an abstract, personal communication with the principal investigator and ZymoGenetics. The data are still preliminary and a more mature version will be released at an upcoming conference this fall (ed. note June 2008).

Discussion of the Three Studies

Although the data are net yet mature or even complete, the early results of these three Phase 1 trials indicate that IL-21 is tolerable, with fewer toxic side effects than, for example, the standard immunotherapy for rcc, high-dose IL-2. It has shown efficacy both as a monotherapy and in combination with sorafenib, but again, these are only Phase 1 trials. So far no drug has demonstrated the durable complete responses, albeit in only 7% of patients, that IL-2 has. It is not clear that the maximum tolerated dose, in any of the trials, has yet been established. In any case, it is worthy of further testing in kidney cancer. Unfortunately, the only active plans to test IL-21 are with sorafenib in the Phase 2 combination trial, which opened recruitment in January 2008. ZymoGenetics expects to enroll 30 patients in this trial phase at the 30 μg/kg dose.

One final comment. IL-21 is prescribed over a limited treatment course unlike the targeted therapies, which must be taken continuously in order to maintain their effectiveness. This feature of IL-21 is both good and bad. While a patient may avoid the toxic side effects that inevitably accompany these drugs, the efficacy may wear off after a period of time. In the Thompson trial, we saw that there were 4 partial responders, all of whom eventually progressed after: 5 months, 10 months, 12 months, and 18½ months. For those who respond to treatment, why not try additional treatments, say at every 3 months, to maintain the patient's immunity?