Results from a number of clinical trials studying car­filz­o­mib for the treat­ment of multiple myeloma were presented at the 2012 American Society of Clinical Oncology (ASCO) annual meeting last weekend.

Findings from three Phase 1/2 clinical trials showed that several carfilzomib (Kyprolis) com­bi­na­tions are effective for newly diagnosed multiple myeloma patients. Researchers involved in each of these clinical trials presented the results during oral presentations at the ASCO meeting.

In addi­tion, early results from several clinical trials presented at the meeting con­tinue to show that car­filz­o­mib is safe and effective in heavily pretreated multiple myeloma patients. These findings were presented during poster sessions at the meeting.

In a presentation accompanying the oral talks about car­filz­o­mib, Dr. Robert Orlowski of the M.D. Anderson Cancer Center in Houston described the results of the three car­filz­o­mib studies in newly diagnosed patients as encouraging.

“These upfront com­bi­na­tions with car­filz­o­mib are certainly showing attractive response rates,” commented Dr. Orlowski.  Compared to pre­vi­ous trials that used Velcade (bor­tez­o­mib) instead of car­filz­o­mib, Dr. Orlowski said, “The depth of response appears to be improved, although longer follow-up is needed.”

“Tolerability may be improved as well, especially with the perspective of neu­rop­athy,” he added.  “But all of the comparator studies with bor­tez­o­mib [Velcade] used intravenous dosing, so I think it would be interesting to repeat those comparator studies using sub­cu­tane­ous Velcade, or weekly and sub­cu­tane­ous Velcade, to get a better comparison in terms of tolerability.”

“For future directions, we certainly need Phase 3 studies to determine the role of these attractive regi­mens,” Dr. Orlowski concluded.

Carfilzomib, which is being developed by Onyx Pharmaceuticals (NASDAQ: ONXX), works similarly to Velcade.  Both are proteasome inhibitors that inhibit the breakdown of proteins in cancer cells, thereby triggering their death.

In September, Onyx submitted an application to the U.S. Food and Drug Administration (FDA) for potential approval of car­filz­o­mib as a treat­ment for re­lapsed and refractory multiple myeloma patients who have had at least two prior ther­a­pies.

In December, however, Onyx announced that the FDA granted “standard review designation” to car­filz­o­mib’s application, rather than “priority review.”  Priority review would have sped up the FDA decision regarding approval of car­filz­o­mib by four months.  Some analysts interpreted the standard review as reflecting potential FDA concerns about the car­filz­o­mib application.

The Oncologic Drugs Advisory Committee, which advises the FDA on the potential approval of new cancer treat­ments, will meet on June 20 to review the car­filz­o­mib application. The FDA will make a final decision about the car­filz­o­mib application by July 27 (see related Beacon news).

Immediately fol­low­ing the presentation of the latest car­filz­o­mib results at ASCO, negative financial analyst reports led Onyx’s stock to drop almost 10 per­cent. The analysts were disappointed with car­filz­o­mib’s performance in myeloma patients resistant to both Velcade and Revlimid (lena­lido­mide), a population critical to the FDA's review of the drug's new drug application.

However, Onyx’s stock recovered in full when more positive analyst assess­ments, citing favorable physician feedback regarding the ASCO results, were issued later in the week.

Along with pomalidomide – a chemical relative of multiple myeloma drugs Revlimid and thalidomide (Thalomid) – car­filz­o­mib is considered one of the most promising new myeloma treat­ments that could be approved by the FDA in the near future.

Details from this year’s ASCO presentations about car­filz­o­mib are summarized below.

Carfilzomib-Revlimid-Dexamethasone In Newly Diagnosed Multiple Myeloma

According to results of a Phase 1/2 clinical trial, a com­bi­na­tion of car­filz­o­mib, Revlimid, and dexamethasone is highly effective and well tolerated in newly diagnosed myeloma patients.

Dr. Jakubowiak from the University of Chicago presented the results at ASCO.  Earlier results from the study were presented at the American Society of Hematology annual meeting in December (see related Beacon news).

A total of 53 patients with a median age of 59 years were enrolled in the study.

All patients received between 20 and 36 mg/m² of car­filz­o­mib intravenously on days 1, 2, 8, 9, 15, and 16 for the first eight 28-day cycles. After that, car­filz­o­mib was given only on days 1, 2, 15, and 16 for up to another 16 cycles. All patients also received 25 mg of Revlimid daily during each cycle. In addi­tion, trial participants received 40 mg of dexa­meth­a­sone weekly during the first four cycles, and 20 mg of dexa­meth­a­sone weekly for sub­se­quent cycles.

After a median follow-up of 14 months, 98 per­cent of patients have responded to the treat­ment.  Specifically, 62 per­cent achieved a complete response (42 per­cent achieved a stringent complete response), 19 per­cent a very good partial response, and 17 per­cent a partial response.

Dr. Jakubowiak also reported that responses con­tinued to improve with longer treat­ment.  For patients who completed eight cycles of treat­ment, 61 per­cent achieved a stringent complete response.

In addi­tion, 91 per­cent of patients who achieved a complete response had no evidence of residual disease, and all patients who achieved a stringent complete response were still in remission after a median of nine months.

The pro­gres­sion-free survival rate was 97 per­cent at one year and 92 per­cent at two years.

Among patients who received more than eight cycles of the com­bi­na­tion ther­apy, the most common side effects were low lymphocyte counts (30 per­cent), low leukocyte counts (26 per­cent), and fatigue (25 per­cent).  In addi­tion, Dr. Jakubowiak reported that periph­eral neu­rop­athy was limited, with 11 per­cent of patients developing mild periph­eral neu­rop­athy.

“[Carfilzomib-Revlimid-dexamethasone] is well tolerated and highly active in frontline myeloma with rapid and deep responses in these patients.  Responses con­tinue to deepen with time,” concluded Dr. Jaku­bowiak.  “Importantly, responses appear to be durable.”

He also said that “These results compare favorably to the best results with other frontline induction regi­mens and with sequential au­tol­o­gous trans­plant plus post-transplant consolidation.”

Dr. Orlowski agreed with Dr. Jakobowiak’s conclusions. “We saw a very interesting and powerful combi­nation using car­filz­o­mib with lena­lido­mide [Revlimid] and dexa­meth­a­sone,” said Dr. Orlowski.  “It had nice efficacy and durability data with a very good pro­gres­sion-free survival at one year as well as two years.”

Carfilzomib-Cyclophosphamide-Thalidomide-Dexamethasone For Newly Diagnosed Multiple Myeloma

Results of another Phase 1/2 clinical trial indicate that a com­bi­na­tion of car­filz­o­mib, cyclophosphamide (Cytoxan), thalido­mide, and dexa­meth­a­sone – known as "CYCLONE" – is tolerable and effective in newly diagnosed multiple myeloma patients.

Dr. Joseph Mikhael from the Mayo Clinic in Scottsdale, Arizona, presented results from the Phase 2 portion of the trial at ASCO.

The Phase 2 portion of the study included 27 trans­plant-eligible patients with a median age of 65 years.

All patients received 20 mg/m² of car­filz­o­mib on days 1, 2, 8, 9, 15, and 16 of the first 28-day cycle, and 27 mg/m² of car­filz­o­mib in sub­se­quent cycles. Moreover, all patients received 300 mg/m² of oral cyclophos­phamide on days 1, 8, and 15; 100 mg of oral thalido­mide daily; and 40 mg of oral dexa­meth­a­sone on days 1, 8, 15, and 22 of each cycle.

Twenty-four patients were evaluated for response.

After four cycles of treat­ment, 96 per­cent of the patients responded. Specifically, 29 per­cent achieved a complete response, 46 per­cent a very good partial response, and 21 per­cent a partial response.

After a median follow-up of 8.2 months, 96 per­cent of patients were alive.

Fifty per­cent and 21 per­cent of patients experienced severe and life-threatening side effects, respectively.  These included fatigue, low white blood cell counts, blood clots, and muscle weakness.

In addi­tion, over 20 per­cent of patients experienced fatigue, con­sti­pa­tion, low platelet counts, and weakness.

Twenty-nine per­cent of patients developed mild periph­eral neu­rop­athy.

All patients who chose to collect stem cells were able to collect enough for trans­plan­ta­tion.

Dr. Mikhael concluded, “CYCLONE is highly effective with an over­all response rate of 96 per­cent with only four cycles.”  He also said that the regi­men is well tolerated with man­ageable suppression of blood cell counts and no more than mod­er­ate periph­eral neu­rop­athy.

Since the dose of car­filz­o­mib used in the trial was well tolerated and other car­filz­o­mib trials have indicated that higher doses are also well tolerated, Dr. Mikhael said that more patients will be recruited to receive CYCLONE using higher doses of car­filz­o­mib.

Dr. Orlowski said that the response rate for CYCLONE is similar to other three- and four-drug regi­mens.  He pointed out, however, that a pre­vi­ous study showed that the addi­tion of Revlimid to Velcade-cyclophosphamide-dexamethasone does not appreciably improve efficacy.  He therefore suggested testing car­filz­o­mib, cyclophosphamide, and dexa­meth­a­sone without thalido­mide to see how the response rates compare and to reduce the risk of periph­eral neu­rop­athy.

Carfilzomib-Melphalan-Prednisone In Elderly Patients With Newly Diagnosed Multiple Myeloma

Dr. Philippe Moreau from the University Hospital in Nantes, France, gave the remaining oral presentation at ASCO with car­filz­o­mib-related trial results.

Dr. Moreau reviewed results of a recent Phase 1/2 study conducted in France.  The results show that a frontline com­bi­na­tion of car­filz­o­mib, melphalan (Alkeran), and prednisone is tolerable and effective in newly diagnosed myeloma patients over the age of 65.

The goal of the French study was to determine the maximum tolerated dose of car­filz­o­mib when used in com­bi­na­tion with mel­phalan and pred­ni­sone in elderly myeloma patients.

Twenty-four myeloma patients were enrolled in the Phase 1 portion of the clinical trial.

Patients were randomly assigned to receive one of four different car­filz­o­mib doses: 20 mg/m², 27 mg/m², 36 mg/m², or 45 mg/m² of car­filz­o­mib admin­istered intravenously on days 1, 2, 8, 9, 22, 23, 29, and 30 for nine 42-day cycles. In addi­tion, all patients received 9 mg/m² of oral mel­phalan and 60 mg/m² of pred­ni­sone on days 1 to 4 of each cycle.

The researchers observed dose-limiting toxicities in two patients who received 45 mg/m² of car­filz­o­mib. A dose-limiting toxicity was defined as a severe blood toxicity that prevented the patient from receiving car­filz­o­mib on at least two days during the first treat­ment cycle. The researchers therefore concluded that the maximum tolerated dose of car­filz­o­mib was 36 mg/m².

Additional patients have been and will con­tinue to be recruited for the Phase 2 portion of the clinical trial, bringing the total number of patients who will be enrolled to 50.

Currently, 43 patients have been enrolled and 35 patients, with a median age of 74 years, were evaluated for response.

After a median of eight cycles of treat­ment, 89 per­cent of patients responded to the treat­ment regi­men, with 3 per­cent achieving a complete response, 40 per­cent a very good partial response, and 46 per­cent a partial response.

The pro­gres­sion-free survival was 81 per­cent and over­all survival was 94 per­cent after a median follow-up of one year.

The most common severe side effects were in­fec­tions (15 per­cent), blood clots in the veins (6 per­cent), or atrial fibrillation (irregular heart beat, 6 per­cent).

Notably, only 3 per­cent of patients developed periph­eral neu­rop­athy.

Dr. Orlowski commented in his discussion presentation, “Certainly, it looks like car­filz­o­mib-melphalan-prednisone should prove to be a better tolerated regi­men from the perspective of neu­rop­athy.”  In the Phase 1/2 study of Velcade-melphalan-prednisone, conducted a number of years ago, 17 per­cent of patients developed periph­eral neu­rop­athy.

In the conclusion to his presentation, Dr. Moreau said he considered the over­all response rate for this com­bi­na­tion to be very promising.

In addi­tion, Dr. Moreau said, “These results compare favorably with other com­bi­na­tions used as routine treat­ment for frontline ther­apy for elderly patients.”

He pointed out that pre­vi­ous studies found over­all response rates in elderly patients to be 71 per­cent for Velcade-melphalan-prednisone, 76 per­cent for thalido­mide-melphalan-prednisone, 80 per­cent for Revlimid-melphalan-prednisone, and 85 per­cent for Revlimid plus dexamethasone (Decadron).

Dr. Orlowski cautioned, “It is a little bit dangerous to compare across studies at this point,” because all of these studies include a small number of patients and comparator studies were designed differently.  However, he stated that the response rates seem promising.

Single-Agent Carfilzomib In Multiple Myeloma Patients Resistant To Velcade And Thalidomide Or Revlimid

A poster presented last Saturday analyzed results from a Phase 2b clinical trial of car­filz­o­mib.  The analysis showed that single-agent car­filz­o­mib dem­onstrated “clinically meaningful, durable responses” in patients who had advanced multiple myeloma.

The original study included a total of 266 re­lapsed or refractory myeloma patients.  The researchers then analyzed the out­comes of specific patients within the study who had advanced disease.

In particular, they analyzed out­comes of 228 patients (86 per­cent) who were either intolerant or refractory (resistant) to Velcade as well as Revlimid or thalido­mide (referred to as “double refractory/intolerant”).

They also analyzed out­comes of a subgroup of 44 patients (17 per­cent) who were refractory to all classes of myeloma treat­ments.  This includes alkylators such as mel­phalan, anthracyclines such as doxorubicin (Adriamycin), corticosteroids such as dexa­meth­a­sone, immuno­modu­la­tory agents such as Revlimid and thalido­mide, and proteasome inhibitors such as Velcade.

Across all patients in the study, the median time since diag­nosis was 5.4 years.

The results show that patients refractory to prior myeloma ther­a­pies had responses similar to the entire group of patients included in the study.

Specifically, over­all response rates were 23 per­cent over­all, 21 per­cent for those who were double refractory/intolerant, and 20 per­cent for those refractory to all classes of myeloma ther­a­pies.

Responses lasted 7.8 months for the entire study group, 7.4 months for the double refractory/intolerant group, and 7.8 months for those refractory to all classes of treat­ment.

Carfilzomib In Myeloma Patients Resistant To Velcade

Another poster highlighted results of a Phase 1/2 clinical trial on the safety and efficacy of car­filz­o­mib as a replacement ther­apy for Velcade in patients who progressed while taking Velcade-containing regi­mens. Early results of the study suggest that car­filz­o­mib is an effective and tolerable replacement for Velcade in these patients.

The study included 27 patients who had received a median of six pre­vi­ous lines of ther­apy, with a median of 2.5 of those containing Velcade.  All patients included in the study had progressed on their last Velcade-containing regi­men.

After pro­gres­sion, patients con­tinued on their same treat­ment regi­mens, except intravenous car­filz­o­mib was given in place of Velcade.

Twenty-two of the patients were evaluated for a response after a median of three cycles of car­filz­o­mib ther­apy.  The over­all response rate was 51 per­cent, with 23 per­cent of patients achieving a complete response, 5 per­cent a very good partial response, and 23 per­cent a partial response.

The median pro­gres­sion-free survival time was 9.8 months.

The most common severe side effects were low platelet counts (32 per­cent), low lymphocyte counts (17 per­cent), low red blood cell counts (9 per­cent), fever (9 per­cent), sepsis (9 per­cent), and pneu­monia (9 per­cent).

Blood Safety Data For Carfilzomib In Relapsed/Refractory Multiple Myeloma

Another poster summarized results of an analysis of the safety of car­filz­o­mib in re­lapsed or refractory myeloma patients.

Based on their results, the study investigators concluded that the blood safety profile of car­filz­o­mib was similar to or better than that of cur­rently approved myeloma ther­a­pies.

In their analysis, the researchers assessed the rate of various blood-related side effects in 526 myeloma patients treated with single-agent car­filz­o­mib across four different Phase 2 studies.

According to the researchers, blood-related side effects were common, with 70 per­cent of patients treated with car­filz­o­mib experiencing blood-related side effects.

The most common blood-related side effects included low red blood cell counts (47 per­cent), low platelet counts (38 per­cent), low lymphocyte counts (26 per­cent), and low neutrophil counts (23 per­cent).

However, they found that severe to life-threatening blood-related side effects were both infrequent and lasted for short periods of time.

The most common severe to life-threatening side effects included low red blood cell counts (22 per­cent), low platelet counts (25 per­cent), low lymphocyte counts (20 per­cent), and low neutrophil counts (12 per­cent).

The results showed that patients rarely dis­con­tinued ther­apy or required dose reductions because of blood-related side effects.

Carfilzomib Plus Panobinostat For Relapsed And Refractory Multiple Myeloma

The final car­filz­o­mib-related poster described an ongoing Phase 1/2 clinical trial that is cur­rently recruiting participants. The goal of this study is to evaluate the safety and efficacy of car­filz­o­mib in com­bi­na­tion with panobinostat for the treat­ment of re­lapsed and refractory multiple myeloma.

Panobinostat is an oral drug that is being developed by the pharma­ceutical com­pany Novartis (NYSE: NVS) for a variety of different cancers, including multiple myeloma. It belongs to a class of drugs called histone deacetylase inhibitors, which work by increasing the pro­duc­tion of proteins that slow cell division and cause cell death. Preclinical studies have shown that histone deacetylase inhibitors enhance the anti-myeloma activity of proteasome inhibitors such as car­filz­o­mib.

The study plans to enroll up to 52 re­lapsed or refractory myeloma patients.

The Phase 1 portion of the study will include approx­i­mately 24 patients and will determine the maximum tolerated dose of car­filz­o­mib and panobinostat when admin­istered together.

In the Phase 2 portion of the study, approx­i­mately 25 patients will receive treat­ment with the optimal doses of the car­filz­o­mib-panobinostat com­bi­na­tion. Researchers will then evaluate the over­all response rate, time to pro­gres­sion, pro­gres­sion-free survival, and over­all survival of patients treated with this regi­men as well as the safety of the regi­men.

For more in­­for­ma­tion, please see abstracts 8009, 8010, 8011, 8035, 8086, 8098, and TPS8115 on the ASCO meeting website.  In addi­tion, as a courtesy to The Beacon's readers, Dr. Orlowski has made his review presentation (Powerpoint format) about the results of the three car­filz­o­mib oral presentations available for download and viewing.