New Data on Horizon in Several Key Areas

OncologyLive, November 2012, Volume 13, Issue 11

Although new therapies have revolutionized the management of certain hematologic malignancies during the past 15 years, clinical trials currently under way hold the potential to yield new targeted agents and better treatment strategies.

Andrew D. Zelenetz, MD, PhD

Although new therapies have revolutionized the management of certain hematologic malignancies during the past 15 years, clinical trials currently under way hold the potential to yield new targeted agents and better treatment strategies.

For insight into emerging strategies in this complex arena, OncologyLive touched base with Andrew D. Zelenetz, MD, PhD, chief of Lymphoma Service and vice chairman of Medical Informatics at Memorial Sloan-Kettering Cancer Center in New York City. He helped develop several of the new agents approved for the treatment of lymphoma, including bortezomib (Velcade), and continues to play a leading role in ongoing clinical trials.

Zelenetz serves as program director of the 17th Annual International Congress on Hematologic Malignancies, scheduled for February 15-17, 2013, in New York City, where experts will discuss the implications of research advances. The congress is hosted by Physicians’ Education Resource (PER).

Ibrutinib Study Results Slated for Release

Speaking in advance of the American Society of Hematology (ASH) meeting, scheduled for December 8-11 in Atlanta, Georgia, Zelenetz discussed several new agents in development and recent trends he finds significant.The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, which promotes apoptosis and inhibits cell migration and adhesion, is being explored in several different hematologic malignancies. It is the most developed of a group of new agents under study in chronic lymphocytic leukemia (CLL), where the FDA has granted Fast Track designation in patients with relapsed or refractory disease after at least one prior therapy.

Zelenetz said that the drug has demonstrated dramatic activity in CLL, noting that data presented earlier this year confirmed its activity and paved the way for important studies yet to come.

At the European Hematology Association (EHA) Congress in June, the results were presented from a phase IB/II study that evaluated singleagent ibrutinib in patients who were either treatmentnaïve or relapsed/refractory after at least two lines of therapy. The observed overall response rate for patients who had received a 420-mg daily dose of ibrutinib was 67% in patients who were relapsed or refractory at a median follow-up of 12.6 months, and 73% among treatmentnaïve patients at a median follow-up of 10.7 months.1

Pharmacyclics, the company developing ibrutinib, announced that updates on this trial as well as eight others involving the agent have been accepted for presentation during ASH 2012. The company’s clinical development program involves a variety of hematologic malignancies (Table).2

Table. Ongoing Clinical Trials of Ibrutinib (PCI-32765)

Main Malignancy Typea

Description

Status

B-cell lymphoma

Dose-escalation study

Phase I (NCT00849654)

B-cell lymphoma Chronic lymphocyctic leukemia

Safety, fixed-dose study

Phase I (NCT01109069)

Chronic lymphocyctic leukemia Small lymphocytic lymphoma

Safety, optimal-dose study

Ibrutinib plus fludarabine/ cyclophosphamide/rituximab vs ibrutinib plus bendamustine/rituximab

Ibrutinib plus ofatumumab

Phase I/II (NCT01105247)

Phase I/II (NCT01292135)

Phase I/II (NCT01217749)

Diffuse large B-cell lymphoma

Safety, efficacy study

Phase II (NCT01325701)

Mantle cell lymphoma

Monotherapy for 2 cohorts: Patients who failed bortezomib and patients who are bortezomib-naïve

Phase II (NCT01236391)

Multiple myeloma

Safety, clinical benefit rate at 3 different dosages, with and without dexamethasone

Phase II (NCT01478581)

aSome trials include related hematologic malignancies.

Sources

Clinical trials overview. Pharmacyclics website, pharmacyclics.com. Accessed November 6, 2012.

ClinicalTrials.gov website. ClinicalTrials.gov. Accessed November 6, 2012.

Of these studies, Zelenetz highlighted a diffuse large B-cell lymphoma (DLBCL) trial as one that could potentially change treatment. The phase II trial is evaluating whether ibrutinib has preferential activity in the ABC subtype of relapsed/refractory DLBCL.

Currently, the standard treatment for this disease is the R-CHOP regimen, a combination of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone. If ibrutinib demonstrates positive activity, it might offer patients another treatment option.

Small-Molecule Agents Explored in CLL

Meanwhile, the drug’s performance in multiple myeloma is disappointing, according to Pharmacyclics. The company said a small study indicated that 420 mg of single-agent ibrutinib was tolerable but did not produce defined objective responses, and that the drug would be tested at higher dosages. These results also will be reported at ASH, the company said.Early-phase clinical trials into several new agents may hold promise in CLL, Zelenetz noted. “In the area of CLL, things have been exciting,” he said. In addition to the ibrutinib research involving CLL, Zelenetz pointed to three small molecules under study: GS-1101 (formerly known as CAL-101), IPI-145, and ABT-199.

GS-1101 is a potent PI3K delta inhibitor that targets a signaling pathway implicated in malignant B-cell proliferation. The drug has been explored as a monotherapy and in combination with other agents. In the results of a phase I combination study that were presented at ASH 2011, a substantial majority of patients in the trial experienced reductions in lymphadenopathy, including a ≥50% decrease in lymph node area in >75% of patients on all regimens, and more than 80% of patients receiving each regimen met criteria for CLL response.3

Another PI3K inhibitor, IPI-145, is a gamma/delta selective drug that appears to be a slightly less-selective inhibitor than GS-1101, said Zelenetz. “Theoretically, the drug should have activity both in B-cell lymphomas and in T-cell lymphomas,” he said. “That should be exciting.”

Infinity Pharmaceuticals, the manufacturer of IPI-145, announced that data from its ongoing phase I trial in patients with advanced hematologic malignancies, including CLL, are scheduled to be presented at ASH 2012.4

Cord Blood Research on Radar

ABT-199 inhibits bcl-2, a protein that deregulates apoptosis in cancer cells. In early study results presented at this year’s EHA meeting, activity has been observed in patients who received ABT-199, including reduction in leukemia counts, reduction in lymph node size, and an induction of apoptosis in CLL cells.5 “It looks like it has pretty substantial activity in CLL, but we’ll see how much, and we’ll see if there’s any activity in non-Hodgkin lymphoma as well,” Zelenetz said.In the area of cord blood transplantation, Zelenetz is interested in any new findings that may emerge on the number of matching units needed for successful outcomes in adults with hematologic malignancies.

In 2005, researchers at the University of Minnesota demonstrated that transplantation of two partially human leukocyte antigen (HLA)-matched umbilical cord blood units achieved positive results in adult patients with various leukemia subtypes, similar to outcomes in pediatric patients who may only require one cord blood unit.6

“The pioneering work done at the University of Minnesota demonstrated that if you use multiple cord bloods, you could transplant adults,” Zelenetz said. “However, one of the questions that remains is: Do you really need to use two cord bloods?”

OncLive TV Exclusive

Dr Andrew Zelenetz Previews the 2012 ASH Annual Meeting

Zelenetz said that the use of more cord blood consumes valuable resources. Many patients do best when the cord blood comes from a relative or a related donor. However, estimates have indicated that as many as 30% of patients are unable to find cord blood donors among the 10 million people who are listed as donors, according to the American Cancer Society.7

Expanding Utility of Brentuximab Vedotin

The Eurocord International Registry on Cord Blood Transplantation in France is conducting a retrospective analysis evaluating the impact of single versus double cord blood transplantation in adults with acute myeloid leukemia or acute lymphoblastic leukemia.Last year’s approval of brentuximab vedotin (Adcetris) represented a major advancement in the treatment of Hodgkin lymphoma (HL), a disease for which the FDA had not approved a new therapy since 1977.

Brentuximab vedotin is an antibody-drug conjugate that selectively targets CD30, an important genetic marker in classic lymphoma and anaplastic large cell lymphoma. It has been approved to treat patients with HL who have relapsed after receiving autologous stem cell transplant (ASCT) therapy or who are not candidates for ASCT and have failed two chemotherapy regimens, as well as for patients with systemic anaplastic large cell lymphoma after failure of chemotherapy.

Zelenetz said the excitement around brentuximab vedotin concerns whether it can be used as a first- or second- line treatment in patients with Hodgkin lymphoma.

A phase III trial currently under way is evaluating the standard doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy regimen versus brentuximab vedotin plus an abbreviated chemotherapy regimen without bleomycin (AVD).8

“The reason bleomycin is eliminated is because an early study combining ABVD with brentuximab vedotin demonstrated unexpected very serious pulmonary toxicity,” Zelenetz said.

The trial, sponsored by Millennium Pharmaceuticals in collaboration with Seattle Genetics, is seeking to enroll more than 1000 patients with treatment-naïve classical HL.

References

  1. O’Brien S, Furman R, Coutre S, et al. The Bruton’s tyrosin kinase inhibitor ibrutinib is highly active and tolerable in relapsed or refractory (R/R) and treatment naïve (TN) CLL patients, updated results of a phase IB/II study. Haematologica. 2012;97(suppl 1:218; abstr 0542).
  2. Pharmacyclics reports fiscal 2013 first quarter financial results and multiple PCI-32765 presentations at the 54th American Society of Hematology Annual Meeting [press release]. Sunnyvale, CA: PRNewswire; November 5, 2012.
  3. Sharman J, de Vos S, Leonard JP, et al. A phase 1 study of the selective phosphatidylinositol 3-kinase-delta (PI3Kδ) inhibitor, CAL-101 (GS-1101), in combination with rituximab and/or bendamustine in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Blood (ASH Annual Meeting Abstracts). 2011;118(21):1787.
  4. Infinity to present IPI-145 phase 1 clinical data at ASH [press release]. Cambridge, MA: BusinessWire. November 5, 2012.
  5. Roberts A, Davids M, Mahadevan D, et al. Selective inhibition of BCL-2 is active against chronic lymphocytic leukemia (CLL): first clinical experience with the BH3-mimetic ABT-199. Haematologica. 2012;97(suppl 1:219; abstr 0546).
  6. Barker JN, Weisdorf DJ, DeFor TE, et al. Transplantation of 2 partially HLAmatched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy [published online ahead of print October 5, 2004]. Blood. 2005;105(3):1343-1347. doi: 10.1182/blood-2004-07-2717.
  7. Snowden RV. Experimental technology improves cord blood transplants for leukemia patients. American Cancer Society website. http://www.cancer.org. Published January 19, 2010. Accessed November 6, 2012.
  8. Phase 3 frontline therapy trial in patients with advanced classical Hodgkin lymphoma. US National Institutes of Health. Available at www.ClinicalTrials.gov website. Updated October 29, 2012. Accessed November 7, 2012.