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Ibrutinib to B-Cell Lymphoma: Here I Come, Mutated or Not

bwt040312 AACR

By Anette Breindl
Science Editor

At last year's annual meeting of the American Society of Hematology, Pharmacyclics Inc.'s PCI-32765 wowed with its ability to fight chronic lymphocytic leukemia. (See BioWorld Today, Dec. 13, 2012.)

This week at the annual meeting of the American Association for Cancer Research, the drug – now named ibrutinib and partnered with Johnson & Johnson unit Janssen Research and Development LLC, in a deal that could ultimately be worth nearly $1 billion – showed its qualities in another type of cancer.

At Sunday's plenary session, the National Cancer Institute's Louis Staudt presented early results from a Phase II trial of ibrutinib in diffuse large B-cell lymphoma, and gave an overview of the preclinical and Phase I data that got the drug into that Phase II trial.

Ibrutinib, he said, is the culmination of more than a decade of basic research – "genomic studies and studies of the molecular biology of these aggressive tumors that have led us to these rational targets."

One of the insights gleaned from that basic research, he said, is what gets diagnosed as diffuse B cell lymphoma "is actually an amalgam of three molecularly distinct diseases."

With a cure rate of 50 percent and a 75 percent three-year progression-free survival rate, the most common subtype of the three, germinal center B cell-like diffuse large B-cell lymphoma can be fairly effectively treated. "But we urgently need new therapies for the others."

The second most common subtype, activated B-cell, or ABC-like diffuse B-cell lymphoma, has a much lower cure rate of only 35 percent to 40 percent. In loss-of-function screens, Staudt and his team identified Bruton's tyrosine kinase as critical for the survival of this type of lymphoma.

But while such functional genomics normally "converges very naturally with structural genomics" that is, sequence a gene identified as critical in a functional assay and "lo and behold, there are mutations" – this was not the case for Bruton's tyrosine kinase.

However, when Staudt and his team went back to the B-cell receptor that activates the kinase, they found that it has activating mutations in about a fifth of ABC lymphomas. Such mutations are "rare or absent" in other subtypes.

Ibrutinib was designed to foil that B-cell receptor activation, and does so by inhibiting Bruton's tyrosine kinase and ultimately shutting off the hyperactive NF-kappaB signaling caused by either B cell receptor activation or another protein, MyD88. But the drug can be effective both in patients that have such mutations, and in patients without them.

Staudt told BioWorld Today that the decision to test ibrutinib in patients with wild-type CD79B (which is part of the B-cell receptor) and MyD88 came from preclinical data showing that B-cell receptor signaling can be activated through other mechanisms than mutations.

Other drugs targeting the B-cell receptor signaling pathway are Avila Therapeutics Inc.'s AVL-292, Syk inhibitors such as Portola Pharmaceuticals Inc.'s P505-15, which is being targeted in rheumatoid arthritis, and CAL-101 (now GS 1101), which Gilead Sciences Inc. bought, with its acquisition of Calistoga Pharmaceuticals Inc. in 2011.

Clearly, Staudt said, the question of whether patients with mutations in the pathway respond better than those without will be a key question in this and future clinical trials of ibrutinib. But with only a pilot study and four responses in 10 patients in the Phase II trial (which ultimately plans to enroll 60 patients) analyzed to date, "I think it's too early to subset."

In other news from the AACR:

• Ariad Pharmaceuticals Inc., of Cambridge, Mass., presented preclinical data showing its pan-Bcr-Abl inhibitor, ponatinib, retained activity against gatekeeper mutants of FLT3, RET, KIT, PDGFR and FGR1, showing that it overcomes resistant gatekeeper mutations well beyond Bcr-Abl that have been shown to cause resistance to other tyrosine kinase inhibitors in acute myeloid leukemia, medullary thyroid cancer, gastrointestinal stromal tumor and rare forms of leukemia. Data from a separate presentation showed that AP26113, its EGFR-ALK inhibitor, inhibits non-small-lung cancer cell lines that express an activating translocation of the ROS1 tyrosine kinase.

• Genprex Inc., of Austin, Texas, presented preclinical data demonstrating that Oncoprex (FUS1 nanoparticles), when combined with AKT inhibitor MK2206, is more effective in suppressing growth in LKB1 mutant tumors than either single agent. The combined treatment resulted in tumor volume reduction of greater than 2.5 times the tumor reduction achieved with MK2206 alone. A Phase I trial of intravenous Oncoprex demonstrated antitumor activity in lung cancer. The company expects to launch a Phase I/II trial of Oncoprex with Tarceva in lung cancer later this year.

• Immunomedics Inc., of Morris Plains, N.J., reported colorectal cancer could be safely, specifically and rapidly targeted with TF2 bispecific antibody and a radiolabeled peptide, with limited toxicity to the patient, according to results from a Phase I trial. TF2 was created using the firm's Dock-and-Lock (DNL) conjugation technology. In separate news, Immunomedics reported the development of two bispecific, hexavalent antibodies for treating breast, pancreatic and other solid tumors. 1R-(E1)-(E1) and 1R-(15)-(15), which also were generated using the firm's DNL conjugation technology, comprise intact hR1 , a humanized antibody targeting Type I insulin-like growth factor receptor. It also presented data showing that new linker CL2A, which links SN-38, the active metabolite of irinotecan, conjugated to a monoclonal antibody, is more stable and only releases free SN-38 inside the tumor cell. In cancer cell lines and animal models of human cancers, antibody-drug conjugates with more inert CL2E linker were significantly less efficacious than those employing CL2A. In another presentation, Immunomedics reported data showing that epratuzumab, a humanized anti-CD22 antibody, produced moderate antibody-dependent cell-mediated cytotoxicity in vitro, with no detectable complement-dependent toxicity.

• Infinity Pharmaceuticals Inc., of Cambridge, Mass., said preclinical data for saridegib (IPI-926), its oral molecule that inhibits Smoothened, showed antitumor activity in models of residual disease, in which malignant cells remain present after primary treatment. The data showed its ability to delay tumor recurrence is time dependent and supported development in ovarian cancer and small-cell lung cancer disease settings.

• MethylGene Inc., of Montreal, disclosed preclinical data of its multi-targeted kinase inhibitor, MGCD265, showing potent inhibition of tumor growth by combining it with erlotinib. The combination was more effective than either drug alone, resulting in tumor regression in the preclinical model of gastric cancer.

• Peregrine Pharmaceuticals Inc., of Tustin, Calif., reported Phase Ib data showing bavituximab in combination with carboplatin and Alimta (pemetrexed, Eli Lilly and Co.) in patients with previously untreated Stage IV non-small-cell lung cancer indicated a promising safety profile comparable to that expected for chemotherapy alone, with three of the initial five patients achieving a partial tumor response. In a separate presentation, the firm reported preclinical data validating the ability of docetaxel to up-regulate exposure of bavituximab's phosphatidylserine target when the drug is used as an imaging agent.

• Threshold Pharmaceuticals Inc., of South San Francisco, reported Phase IIb data of TH-302, a hypoxia-targeted drug, used in combination with gemcitabine compared to gemcitabine alone in first-line advanced pancreatic cancer. Data from the 214-patient trial showed the primary progression-free survival (PFS) efficacy endpoint was met (p = 0.005) with a median increase in PFS from 3.6 months to 5.6 months in patients treated with a 240 mg/m2 or a 340 mg/m2 dose. The greatest efficacy was seen with the higher dose with a median PFS of six months, and a response rate of 27 percent. Also, for a separate indication of soft tissue sarcoma, Threshold received orphan drug designation from the FDA for TH-302.

• Tokai Pharmaceuticals Inc., of Cambridge, Mass., announced its lead candidate galeterone (TOK-001) was well tolerated with minimal side effects and demonstrated efficacy in a Phase I study of castration-resistant prostate cancer patients. Galeterone is an oral small molecule that uses a triple mechanism of action. The company plans to start a Phase II trial later this year.

• Ziopharm Oncology Inc., of New York, reported preclinical data demonstrating significant antitumor activity of interleukin-12 (IL-12) and interferon-alpha, two proteins involved in immune response to cancers, expressed in vivo using a regulated gene system. The study assessed activity in lung and breast cancer mouse models using intratumoral administration of adenovirus with the RheoSwitch Therapeutic System technology, a DNA-based inducible promoter system, for regulated expression of murine IL-12 or murine interferon-alpha. In the cancer model, each therapy, combined with oral administration of a small-molecule activator ligand, INXN-1001, was found to induce significant tumor growth inhibition by day 25. Ziopharm is the exclusive channel partner to Intrexon Corp., of Blacksburg, Va.