Lenalidomide and bevacizumab have antitumor activity in various tumor types. We conducted a phase I study of this combination in patients with advanced cancer.
A "3 + 3" study design was used. Lenalidomide 10 or 20 mg (orally, days 1-21) and bevacizumab 5, 7.5, or 10 mg/kg, (intravenously, every 2 weeks) were given at four escalating dose levels, followed by an expansion phase at the highest maximum tolerated dose (MTD) (1 cycle = 4 weeks). Dose-limiting toxicity (DLT), MTD, adverse events, and clinical outcomes were assessed.
Thirty-one patients were enrolled (median age, 60 years; men, 52 %). The most common tumor types were colorectal carcinoma (n = 11) and melanoma (n = 5). Overall, 105 cycles (median, 2) were administered. No DLTs were observed. The maximum tested dose (level 4) was used in the expansion phase. The most common toxicities were fatigue (n = 7, 23 %) and skin rash (n = 4, 13 %). One patient developed a transient ischemic attack (3.2 %); prophylactic anticoagulation became mandatory in the subsequent 17 treated patients. Of 31 patients, 27 were evaluable for response. Stable disease (SD) was noted in 10 (37 %) patients, including five patients with SD for ≥6 months (tumor types: clear cell sarcoma, germ cell tumor, colorectal carcinoma, and melanoma). The median progression-free survival and overall survival were 2.8 and 5.5 months, respectively.
The combination of lenalidomide with bevacizumab in patients with advanced solid tumors was safe. Prolonged stable disease was noted in selected tumor types, warranting further clinical evaluation.

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CD123 is a subunit of the heterodimeric interleukin-3-receptor (IL-3R) which is widely expressed on human hematologic malignancies including acute myeloid leukemia (AML). In addition, CD123 can be found on the surface of B cell acute lymphoblastic leukemia (B-ALL), hairy cell leukemia, blastic plasmacytoid dendritic cell neoplasm (BPDCN), chronic myeloid leukemia (CML) and Hodgkin’s lymphoma.

Of these malignancies, we are currently investigating CD123 as a target for adoptive cellular immunotherapy in AML since high CD123 expression is associated with enhanced AML blast proliferation, increased resistance of blasts to apoptosis, and poor clinical prognosis.

Acute Myeloid Leukemia (AML), is a cancer of the myeloid line of blood cells characterized by rapid growth of abnormal white blood cells that accumulate in the bone marrow. AML is the most common form of acute leukemia. Although AML is a relatively rare disease there are approximately 20,000 new cases per year in the US and 10,000 deaths per year, accounting for approximately 1.8% of cancer deaths in the US (SEER). AML standard of care involves chemotherapy to induce remission followed by additional chemotherapy or hematopoietic stem cell transplant. Allogeneic stem cell transplantation is the preferred treatment route for AML following a second remission. It can lead to a 5-year disease free survival in 26% of patients. Unfortunately however, currently, only about half of relapsed patients are able to achieve a second remission with traditional chemotherapy agents. Patients who do not achieve a second remission are much less likely to benefit from transplantation and face a poor outcome.

The use of CAR-T immunotherapy in relapsed AML patients may offer the potential to achieve a complete or longer lasting remission. City of Hope developed CD123 targeted CAR-T cells designed to be both activated to proliferate and to kill CD123 expressing tumor cells. The therapy is designed to recognize and eliminate leukemic cells leading to remission in patients with relapsed or refractory AML and could serve as a bridge to potentially curative allogenic stem cell transplant. The manufacturing process genetically modifies T-cells isolated from peripheral blood mononuclear cells to express a CD123-specific, hinge–optimized, CD28 co-stimulatory domain expressing CAR as well as an EGFRt selection/safety marker. The last feature acts a safety switch to allow depletion of CAR-T cells in the patients if needed.

In collaboration with the COH, we have an on-going phase I clinical study to assess the anti-tumor activity and safety of administering CD123 targeted CAR-T cells and are currently treating patients. We will assess the T-cell persistence and determine the potential immunogenicity of the cells to determine a recommended phase II dose.

On April 18, 2016 Mersana Therapeutics, Inc. reported that preclinical data for its new immunoconjugate product candidate, XMT-1536, demonstrated significant anti-cancer activity in non-small cell lung cancer (NSCLC) and ovarian cancer tumor models (Press release, Mersana Therapeutics, APR 18, 2016, View Source [SID:1234513852]). The data were presented today during a poster session at the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA.

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XMT-1536 is a highly potent anti-sodium-dependent phosphate transport protein 2B (anti-NaPi2b) immunoconjugate comprised of an average of 15 auristatin molecules conjugated to XMT-1535, a novel humanized anti-NaPi2b antibody, via the Dolaflexin antibody-drug conjugate (ADC) platform. Dolaflexin is one of Mersana’s proprietary Fleximer immunoconjugate platforms.

"We are encouraged by the durable regressions XMT-1536 achieved in non-small cell lung cancer and ovarian cancer tumor models, as well as the excellent tolerability and pharmacokinetics in non-human primate exploratory toxicology studies," said Donald A. Bergstrom, MD, PhD, Chief Medical Officer of Mersana. "Based on these data, we are advancing XMT-1536 into IND-enabling studies for the treatment of patients with NaPi2b-expressing tumors."

The study evaluated XMT-1536 in non-squamous NSCLC and non-mucinous ovarian cancer tumor models, indications in which NaPi2b is highly expressed. XMT-1536 demonstrated significant efficacy in all four patient-derived xenograft models representative of the target patient populations. In three patient-derived models of NSCLC, including KRAS-mutant NSCLC, XMT-1536 induced tumor regressions after three weekly doses of 3 mg/kg. In an ovarian cancer xenograft model, XMT-1536 induced partial tumor regressions after a single dose of 3 mg/kg, and complete tumor regressions after a single dose of 5 mg/kg or three weekly doses of 3 mg/kg. XMT-1536 was well-tolerated with no evidence of bone marrow toxicity in non-human primates at up to seven times the dose associated with tumor regression in the mouse xenograft models.

"XMT-1536 further validates the ability of Mersana’s Fleximer platform to generate targeted therapies that have the potential to address unmet needs and improve outcomes for patients with cancer. While there have been recent advancements in the treatment of non-small cell lung cancer and ovarian cancer, there remains tremendous need to address the significant proportion of patients who do not derive full benefit from currently available treatments," said Anna Protopapas, President and Chief Executive Officer of Mersana. "We look forward to the continued development of this second product candidate in our growing pipeline of Fleximer-based immunoconjugate therapies, as we prepare to enter the clinic with XMT-1522 this year."

On April 18, 2016 Arrowhead Pharmaceuticals, Inc. (NASDAQ: ARWR) reported that they have presented a poster on ARC-HIF2, its preclinical development program targeting HIF2-α for the treatment of renal cell carcinoma (RCC), at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 (AACR16), in New Orleans (Press release, Arrowhead Pharmaceuticals, APR 18, 2016, View Source [SID:1234510987]). ARC-HIF2 is Arrowhead’s first RNAi therapeutic program to target tissues outside the liver.

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The poster titled, "Novel HIF-2α targeted RNAi therapeutic for renal cell carcinoma" (abstract 2064), describes data from various stages of development of ARC-HIF2, including RNAi trigger selection, HIF2-α target validation, delivery and targeting ligand validation, and multiple RCC tumor models. These data show that important advancements are being made in this program and for Arrowhead’s Dynamic PolyconjugateTM (DPCTM) delivery platform generally, including the following key findings:

Proof-of-concept ligand dependent, functional delivery was demonstrated using the DPC targeted delivery platform
Silencing HIF2-α expression by RNA interference resulted in reduction of HIF-2α regulated genes
In two different RCC tumor bearing mouse models, ARC-HIF2 inhibited tumor growth and promoted tumor cell death and structural degeneration

On April 17, 2016 Precision Biologics, a NantWorks affiliated clinical stage biotechnology company focused on developing therapeutic and diagnostic products for the early detection and treatment of cancer and a participant in the Cancer MoonShot 2020 program, reported it will present a poster titled, "Identification of target and cytotoxicity of novel monoclonal antibody NEO-201 in ovarian and uterine cancer subtypes" at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 (Press release, Precision Biologics, APR 18, 2016, View Source [SID:1234511010]).

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"With better identification of cancer subtypes that express the NEO201 target, we are taking a step closer to personalized medicine for women diagnosed with ovarian and uterine cancer," said Philip M. Arlen, M.D., President & Chief Executive Officer of Precision Biologics, Inc. of Rockville, MD. "Without the visionary support of NantWorks and Dr. Patrick Soon-Shiong, tumor-specific and neo-epitope cytotoxicity research would face a much slower development path, potentially impacting cancer morbidity and mortality rates."

At AACR (Free AACR Whitepaper), Precision Biologics will present preclinical data on the cytotoxic effects of NEO-201 in uterine and ovarian cancers. NEO-201 is an investigational, humanized monoclonal antibody that targets a novel neo-antigen with sequence homology to the tumor-associated antigens (TAA) CEACAM-5 and CEACAM-6, but highly sensitive to epithelial tumors with little cross reactivity to normal tissue. It is being explored as a potential therapy for epithelial malignancies. NEO-201 demonstrates antibody-dependent cellular cytotoxicity and specifically targets cancer tissues with minimal reactivity in normal tissues.

"Accelerating clinical development of neo-epitopes is a key focus of our immunotherapy initiative. Given the complexity of ovarian and uterine cancer and the great unmet need to overcome these cancers which strike women in the prime of their lives, the work that Precision Biologics is doing with NEO-201 to drive combination immunotherapy reinforces why NantWorks and Cancer MoonShot 2020 supports this program," said Patrick Soon-Shiong, M.D., founder of NantWorks and leader of the Cancer MoonShot 2020 program.

Results from in vitro cytotoxicity assays and inhibition of tumor growth in nude mice will be reported, both as single agents and in combination with a Natural Killer cell line. The preclinical data indicate that NEO-201 demonstrates tumor-specific cytotoxicity and provides promise for the development of TAA-directed therapy for ovarian and uterine malignancies.

Presentation Information: Identification of target and cytotoxicity of novel monoclonal antibody NEO-201 in ovarian and uterine cancer subtypes

Monday, April 18, 2016 at 8:00am-12:00pm in Section 25, Poster Board 27, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting, Ernest N. Morial Convention Center, New Orleans, LA.

Abstract Title: # 1496

Author: M. K. Neuman1, L. Hernandez1, X. P. Wang2, O. Saric2, A. Dubeykovskiy2, P. Arlen1,2 and C. M. Annunziata1,1 National Cancer Institute, Bethesda, MD, 2Precision Biologics, Rockville, MD

About Cancer MoonShot 2020
The Cancer MoonShot 2020 Program is one of the most comprehensive cancer collaborative initiative launched to date, seeking to accelerate the potential of combination immunotherapy as the next generation standard of care in cancer patients. This initiative aims to explore a new paradigm in cancer care by initiating randomized Phase II trials in patients at all stages of disease in 20 tumor types in 20,000 patients within the next 36 months. These findings will inform Phase III trials and the aspirational MoonShot to develop an effective vaccine-based immunotherapy to combat cancer by 2020.