Aplastic anemia secondary to dual cancer immunotherapies a physician nightmare: case report and literature review.

BACKGROUND: Treatment with immune checkpoint inhibitors has revolutionized cancer treatment over the past several years. Despite their clinical benefits, a wide range of immune-mediated toxicities can be observed including hematological toxicities. Although, the majority can easily be managed, immune-mediated adverse events rarely can be severe and difficult to approach. Herein, we are reporting a case of very severe aplastic anemia secondary to ipilimumab (I) and nivolumab (N) treatment that failed various treatment including intensive immune suppressive therapy. CASE PRESENTATION: We described a case of a 45-year old white male, heavy smoker presented to the clinic complaining of left flank pain. He was found to have a metastatic renal cell carcinoma for which he was treated with dual immunotherapy and later complicated by severe immune related adverse events. The patient later died after failing intensive immune suppressive therapy. CONCLUSION: Immunotherapy has become an established pillar of cancer treatment improving the prognosis of many patients with variant malignancies. Yet, lethal adverse events can occur in rare cases. It is our duty, as physicians, to remain alert and cautious.

Primary Ewing Sarcoma/Primitive Neuroectodermal Tumor of the Kidney: The MD Anderson Cancer Center Experience.

Limited information exists on the clinical behavior of the Ewing sarcoma family of tumors (ESFT) of the kidney. We reviewed the records of 30 patients (aged 8-69 years) with ESFT of the kidney seen at our institution between 1990 and 2013. We analyzed the event-free survival (EFS) and overall survival (OS) for associations with patient demographics, disease group, tumor size, tumor thrombus, and treatment. Six patients (20%) had tumors confined to the kidney (Group I), seven (23.3%) had local tumor extension beyond the kidney (Group II), and 17 (56.7%) had distant metastasis at diagnosis (Group III). Twenty-five (83.3%) patients underwent radical (19 upfront, five delayed) or partial (one upfront) nephrectomy, 25 (83.3%) chemotherapy and four (13.3%) radiotherapy. The 4-year EFS and OS were 43% (95% CI, 26-61%) and 63% (95% CI, 46-81%), respectively. EFS and OS were significantly associated with disease group and chemotherapy (p < 0.039). The presence of tumor thrombus in renal vein and/or inferior vena cava was associated with worse EFS (p = 0.053). Patients with disease confined to the kidney treated with nephrectomy and adjuvant chemotherapy have favorable outcomes. Local tumor extension beyond the kidney, tumor thrombus, and distant metastasis are unfavorable factors that warrant intensification or novel approaches of therapy.

Circulating tumor DNA analysis in the era of precision oncology.

The spatial and temporal genomic heterogeneity of various tumor types and advances in technology have stimulated the development of circulating tumor DNA (ctDNA) genotyping. ctDNA was developed as a non-invasive, cost-effective alternative to tumor biopsy when such biopsy is associated with significant risk, when tumor tissue is insufficient or inaccessible, and/or when repeated assessment of tumor molecular abnormalities is needed to optimize treatment. The role of ctDNA is now well established in the clinical decision in certain alterations and tumors, such as the epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer and the v-Ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in colorectal cancer. The role of ctDNA analysis in other tumor types remains to be validated. Evolving data indicate the association of ctDNA level with tumor burden, and the usefulness of ctDNA analysis in assessing minimal residual disease, in understanding mechanisms of resistance to treatment, and in dynamically guiding therapy. ctDNA analysis is increasingly used to select therapy. Carefully designed clinical trials that use ctDNA analysis will increase the rate of patients who receive targeted therapy, will elucidate our understanding of evolution of tumor biology and will accelerate drug development and implementation of precision medicine. In this article we provide a critical overview of clinical trials and evolving data of ctDNA analysis in specific tumors and across tumor types.

Management of patients with high-risk and advanced prostate cancer in the Middle East: resource-stratified consensus recommendations.

PURPOSE: Prostate cancer care in the Middle East is highly variable and access to specialist multidisciplinary management is limited. Academic tertiary referral centers offer cutting-edge diagnosis and treatment; however, in many parts of the region, patients are managed by non-specialists with limited resources. Due to many factors including lack of awareness and lack of prostate-specific antigen (PSA) screening, a high percentage of men present with locally advanced and metastatic prostate cancer at diagnosis. The aim of these recommendations is to assist clinicians in managing patients with different levels of access to diagnostic and treatment modalities. METHODS: The first Advanced Prostate Cancer Consensus Conference (APCCC) satellite meeting for the Middle East was held in Beirut, Lebanon, November 2017. During this meeting a consortium of urologists, medical oncologists, radiation oncologist and imaging specialists practicing in Lebanon, Syria, Iraq, Kuwait and Saudi Arabia voted on a selection of consensus questions. An additional workshop to formulate resource-stratified consensus recommendations was held in March 2019. RESULTS: Variations in practice based on available resources have been proposed to form resource-stratified recommendations for imaging at diagnosis, initial management of localized prostate cancer requiring therapy, treatment of castration-sensitive/naïve advanced prostate cancer and treatment of castration-resistant prostate cancer. CONCLUSION: This is the first regional consensus on prostate cancer management from the Middle East. The following recommendations will be useful to urologists and oncologists practicing in all areas with limited access to specialist multi-disciplinary teams, diagnostic modalities and treatment resources.

Basket Trials and the MD Anderson Precision Medicine Clinical Trials Platform.

Precision medicine incorporates information regarding tumor biology involved in patients' carcinogenesis and individualized treatment of patients using drugs that inhibit the molecular basis of their disease. Implementation of precision medicine accelerated the drug approval process, translating discoveries in basic science and biotechnology into patient care. Clinical trials with innovative or adaptive design including "basket" and "umbrella" trials explore personalized therapies against in selected tumor types and/or across tumor types. In 2007, we started the Initiative for Molecular Profiling and Advanced Cancer Therapy, the first precision medicine program across tumor types. We demonstrated that therapy matched to patients' tumor molecular profiling is associated with improved rates of response, progression-free survival, and overall survival compared with nonmatched targeted therapy. We have now entered a new era of precision medicine that includes comprehensive tumor testing and multiple innovative modalities hoping to overcome the complexity of tumor biology to improve patient outcomes.

Defining, Identifying, and Understanding "Exceptional Responders" in Oncology Using the Tools of Precision Medicine.

Widely available molecular profiling technology, including next-generation sequencing has changed the landscape of drug development in cancer. An increasing number of clinical trials in early drug development require patient selection based on molecular alterations. Concurrently, efforts to identify molecular alterations in tumors that exhibited exceptional response after systemic treatment with standard or investigational agents have been published or are in progress. These discoveries may ultimately serve as predictive markers or "actionable mutations" for future therapies. To test the feasibility of collecting the archival tissues from proposed exceptional responder patients and successful subsequent molecular profiling, the National Cancer Institute opened a nationwide exceptional responder initiative protocol in 2014. In addition, an increasing number of exceptional responder cases have been identified and published from academia institutions. The Network of Enigmatic Exceptional Responders study uses crowdsourcing to identify exceptional responders and will molecularly profile tumors to discern molecular correlates with exceptional response. In this review, we discuss the potential role of exceptional responder molecular analysis in new biomarker discovery efforts to further advance precision medicine in oncology therapeutics.

Chronic Myeloid Leukemia in a Patient Receiving Tofacitinib: A Case Report and Literature Review.

BACKGROUND: Tofacitinib is a new oral Janus kinase inhibitor that has shown promising clinical benefit in various rheumatologic diseases. However, many concerns related to the development of malignancies have been reported with its use. CASE PRESENTATION: A 43-year-old female patient received tofacitinib for refractory rheumatoid arthritis (RA). Two years after 5 mg bid daily dosing, the patient developed chronic myelogenous leukemia (CML), for which she received imatinib and tofacitinib was discontinued. She then remained in remission for rheumatoid arthritis and within the expected milestone outcome for her CML. CONCLUSION: This is the first reported case of CML after the use of tofacitinib. This event is of particular interest knowing the possible benefits tofacitinib carries in the treatment of CML demonstrated in a few studies.

Expanded access to investigational drugs: balancing patient safety with potential therapeutic benefits.

INTRODUCTION: Expanded access is the use of an investigational product by patients with serious medical conditions without participation in a clinical trial. It is a complicated process involving the collaboration of many parties and pharmaceutical companies. Ongoing efforts focus on accelerating expanded access procedures in the best interest of patients with cancer. AREAS COVERED: We review the regulatory and ethical challenges encountered in efforts to optimize expanded access. EXPERT OPINION: In the era of personalized medicine, patients may benefit from novel therapeutic agents that demonstrate encouraging results in early studies. However, drug approval is a lengthy and cumbersome procedure that might exceed the time frame of a life-threatening disease. Expanded access provides options to patients with unmet needs. It may provide informative safety and efficacy data to the manufacturers and the scientific and regulatory organizations. Ongoing efforts are being made by global governmental and scientific committees, regulatory agencies, and patient organizations to address the ethical and regulatory issues and to optimize the expanded access process. Their goal is to expand access to promising novel drugs for individual patients and to accelerate the necessary procedures while preserving patient safety.

Obinutuzumab for the treatment of chronic lymphocytic leukemia and other B-cell lymphoproliferative disorders.

INTRODUCTION: Chemoimmunotherapeutic regimens using the anti-CD20 antibody rituximab improved significantly the survival rates in various B-cell lymphoproliferative disorders (LPDs), including chronic lymphocytic leukemia (CLL). The next-generation CD20 antibody obinutuzumab represents an addition to the drug armamentarium used for the therapeutic management of patients with LPDs. Areas covered: Herein, the authors discuss the biochemical and conformational engineering of obinutuzumab to increase antibody-dependent cell-mediated cytotoxicity and direct cell death. They also describe the available preclinical data on obinutuzumab's role in B-cell LPDs. Furthermore, the authors summarize the Phase I and II clinical trials of obinutuzumab, focusing on the main pharmacokinetic/pharmacodynamic characteristics, the most common clinically significant adverse events, dose optimization, and clinical outcomes of patients with CLL and other B-cell LPDs treated with obinutuzumab as monotherapy or in combination with other agents. To put these data in perspective, the use of obinutuzumab is compared with that of rituximab in CLL and other B-cell LPDs. Expert opinion: Clinical trials have demonstrated that obinutuzumab is well tolerated. The novel mechanism of action of obinutuzumab is associated with significant efficacy in CLL and other B-cell LPDs. Ongoing clinical trials are expected to determine the optimal use of obinutuzumab in these diseases.

Phase I clinical trial of lenalidomide in combination with bevacizumab in patients with advanced cancer.

PURPOSE: Lenalidomide and bevacizumab have antitumor activity in various tumor types. We conducted a phase I study of this combination in patients with advanced cancer. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Phase I clinical trial of lenalidomide in combination with 5-fluorouracil, leucovorin, and oxaliplatin in patients with advanced cancer.

PURPOSE: Lenalidomide has synergistic anticancer effects when used with chemotherapy. We conducted a phase I study of lenalidomide in combination with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) in patients with advanced cancer. METHODS: A "3 + 3" study design was used. Lenalidomide was given orally on days 1-14, oxaliplatin and leucovorin were given intravenously on day 1, and 5-fluorouracil was given as a continuous infusion on days 1-2. The dose escalation phase of the study was followed by an expansion phase. We assessed the maximum tolerated dose, dose-limiting toxicities, and response. RESULTS: Thirty-eight patients were treated [median age 53 years (range 31-76); male/female 20:18]. The most common diagnosis was colorectal cancer (CRC) (n= 30, 79%). Overall, 132 cycles (median 2/patient) were administered. No dose-limiting toxicities were observed. The maximum tested dose (dose level 4) was used in the expansion phase. Grade 3/4 treatment-related toxicities (all reversible) were seen in 14 (37%) patients and included neutropenia (n = 11), thrombocytopenia (n = 2), and fatigue (n = 2). There were no thrombotic events. Response was evaluable in 32 patients: 19 (59%) had stable disease (SD), including SD ≥ 6 months in 4 (13%) patients. Tumor types with SD ≥ 6 months were CRC (n = 2; progression-free survival [PFS] 11.3 and 7.1 months, respectively), gastric (n = 1; PFS 8.5 months), and pancreatic (n = 1; PFS 6.4 months) cancer. The median PFS and overall survival durations were 2.2 months (range <1.3-23) and 5.5 months (range <1.6-23), respectively. CONCLUSIONS: Lenalidomide in combination with FOLFOX was well tolerated. Four patients had prolonged stable disease. This combination merits further investigation for selected patient populations.

Dose-finding study of hepatic arterial infusion of irinotecan-based treatment in patients with advanced cancers metastatic to the liver.

BACKGROUND: Liver metastases are associated with a poor prognosis. We investigated the use of hepatic arterial infusion (HAI) of irinotecan combination therapy in patients with liver metastases. PATIENTS AND METHODS: Patients with histologically confirmed advanced cancer with liver metastases that was refractory to standard therapy were eligible. A standard "3 + 3" phase I study design was used to determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD). Three cohorts were evaluated: HAI of irinotecan with systemic intravenous (IV) (a) bevacizumab, (b) oxaliplatin and bevacizumab, or (c) bevacizumab and cetuximab. RESULTS: From October 2009 through December 2013, 98 patients with various tumor types were enrolled (median age, 62 years, range, 34-85; and median number of prior therapies, 4, range, 1-11). In cohorts A and C, dose escalation continued until the highest dose level-considered the MTD-was reached. In cohort B, dose escalation continued until dose level 3, and dose level 2 was considered the MTD. Rates of grade 3/4 adverse events were as follows: diarrhea, 8 %; fatigue, 4 %; neutropenia, 4 %; thrombocytopenia, 2 %; and skin rash, 2 %. Seventy-seven patients were evaluable for response. Partial response was noted in 5 (6.5 %) patients (neuroendocrine cancer, n = 2; CRC, n = 2; NSCLC, n = 1); and stable disease ≥ 6 months in 17 (22.1 %) patients (CRC, n = 13; breast, n = 1; neuroendocrine, n = 1; NSCLC, n = 1; pancreatic, n = 1). CONCLUSIONS: HAI irinotecan in combination with bevacizumab; oxaliplatin plus bevacizumab; or cetuximab plus bevacizumab was safe and may be a treatment option for selected patients with advanced cancer and liver involvement.

Phase I study of azacitidine and oxaliplatin in patients with advanced cancers that have relapsed or are refractory to any platinum therapy.

BACKGROUND: Demethylation process is necessary for the expression of various factors involved in chemotherapy cytotoxicity or resistance. Platinum-resistant cells may have reduced expression of the copper/platinum transporter CTR1. We hypothesized that azacitidine and oxaliplatin combination therapy may restore platinum sensitivity. We treated patients with cancer relapsed/refractory to any platinum compounds (3 + 3 study design) with azacitidine (20 to 50 mg/m(2)/day intravenously (IV) over 15 to 30 min, D1 to 5) and oxaliplatin (15 to 30 mg/m(2)/day, IV over 2 h, D2 to 5) (maximum, six cycles). Platinum content, LINE1 methylation (surrogate of global DNA methylation), and CTR1 expression changes (pre- vs. post-treatment) were assessed. Drug pharmacokinetics were analyzed. RESULTS: Thirty-seven patients were treated. No dose-limiting toxicity (DLT) was noted at the maximum dose. The most common adverse events were anemia and fatigue. Two (5.4%) patients had stable disease and completed six cycles of therapy. Oxaliplatin (D2) and azacitidine (D1 and 5) mean systemic exposure based on plasma AUCall showed dose-dependent interaction whereby increasing the dose of oxaliplatin reduced the mean azacitidine exposure and vice versa; however, no significant differences in other non-compartmental modeled parameters were observed. Blood samples showed universal reduction in global DNA methylation. In tumor samples, hypomethylation was only observed in four out of seven patients. No correlation between blood and tumor demethylation was seen. The mean cytoplasmic CTR1 score decreased. The pre-dose tumor oxaliplatin levels ranged from <0.25 to 5.8 µg/g tumor. The platinum concentration increased 3- to 18-fold. No correlation was found between CTR1 score and oxaliplatin level, which was found to have a trend toward correlation with progression-free survival. CONCLUSIONS: Oxaliplatin and azacitidine combination therapy was safe. CTR1 expression was not correlated with methylation status or tissue platinum concentration.

Outcomes of patients with advanced cancer and KRAS mutations in phase I clinical trials.

BACKGROUND: KRAS mutation is common in human cancer. We assessed the clinical factors, including type of KRAS mutation and treatment, of patients with advanced cancer and tumor KRAS mutations and their association with treatment outcomes. METHODS: Patients referred to the Phase I Clinic for treatment who underwent testing for KRAS mutations were analyzed. RESULTS: Of 1,781 patients, 365 (21%) had a KRAS mutation. The G12D mutation was the most common mutation (29%). PIK3CA mutations were found in 24% and 10% of patients with and without KRAS mutations (p<0.0001). Of 223 patients with a KRAS mutation who were evaluable for response, 56 were treated with a MEK inhibitor-containing therapy and 167 with other therapies. The clinical benefit (partial response and stable disease lasting ≥6 months) rates were 23% and 9%, respectively, for the MEK inhibitor versus other therapies (p=0.005). The median progression-free survival (PFS) was 3.3 and 2.2 months, respectively (p=0.09). The respective median overall survival was 8.4 and 7.0 months (p=0.38). Of 66 patients with a KRAS mutation and additional alterations, higher rates of clinical benefit (p=0.04), PFS (p=0.045), and overall survival (p=0.02) were noted in patients treated with MEK inhibitor-containing therapy (n=9) compared to those treated with targeted therapy matched to the additional alterations (n=24) or other therapy (n=33). CONCLUSIONS: MEK inhibitors in patients with KRAS-mutated advanced cancer were associated with higher clinical benefit rates compared to other therapies. Therapeutic strategies that include MEK inhibitors or novel agents combined with other targeted therapies or chemotherapy need further investigation.

Characteristics and survival of patients with advanced cancer and p53 mutations.

P53 mutations are associated with invasive tumors in mouse models. We assessed the p53mutations and survival in patients with advanced cancer treated in the Phase I Program. Of 691 tested patients, 273 (39.5%) had p53 mutations. Patients with p53 mutations were older (p<.0001) and had higher numbers of liver metastases (p=.005). P53 mutations were associated with higher numbers of other aberrations; PTEN (p=.0005) and HER2 (p=.003)aberrations were more common in the p53 mutation group. No survival difference was observed between patients with p53 mutations and those with wild-type p53. In patients with wild-type p53 and other aberrations, patients treated with matched-therapy against the additional aberrations had longer survival compared to those treated with non-matched-therapy or those who received no therapy (median survival, 26.0 vs. 11.8 vs. 9.8 months, respectively; p= .0007). Results were confirmed in a multivariate analysis (p= .0002). In the p53 mutation group with additional aberrations, those who received matched-therapy against the additional aberrations had survival similar to those treated with non-matched-therapy or those who received no therapy (p=.15). In conclusion, our results demonstrated resistance to matched-targeted therapy to the other aberrations in patients with p53 mutations and emphasize the need to overcome this resistance.

Evaluation of a novel blood pressure scoring method and its association with clinical response in cancer patients treated with anti-vascular endothelial growth factor therapy.

BACKGROUND: The purposes of this study were to establish a novel blood pressure (BP) scoring method and to correlate it with clinical response in advanced cancer patients treated with anti-vascular endothelial growth factor (VEGF) therapies. METHODS: We retrospectively analyzed data for 368 patients from 23 clinical trials that included at least one anti-VEGF agent. We determined BP scores using the traditional Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and our novel method that considers both BP readings and number of anti-hypertensive medications the patient received. BP scores were categorized at baseline and four months. Logistic regression analysis correlated elevated scores with clinical response. Agreement between the CTCAE and the new method was assessed. RESULTS: Under the new BP scoring method, partial response rates were 20 % in patients with an elevated score at four months versus 6 % in patients without elevated score (P < 0.001). When adjusted for tumor type, age, sex, history of anti-VEGF treatment, and number of anti-VEGF treatments, elevated BP under the new scoring method had an odds ratio of 3.8 (95 % confidence interval [CI]: 1.8, 8.2; P < 0.001). The kappa statistic for agreement between the CTCAE and new scoring methods was 0.57 (95 % CI: 0.47, 0.67; P < 0.001), indicating significant concordance. CONCLUSION: Using the novel scoring method, an increase in BP scores was a marker for favorable clinical response in patients who received anti-VEGF treatment. This new method ultimately provides information with regard to clinical tumor response over and above that provided by the CTCAE scoring method.

Pharmacokinetic evaluation of vincristine for the treatment of lymphoid malignancies.

INTRODUCTION: Vincristine is a key agent for the treatment of acute lymphoblastic leukemia (ALL) and other lymphoid malignancies. The strong antineoplastic activity of vincristine has been limited by its pharmacological characteristics. AREAS COVERED: This paper reviews the role of vincristine in the treatment of lymphoid malignancies. This review summarizes its efficacy and toxicity, and focuses on the pharmacokinetic features of vincristine that affect clinical outcomes. EXPERT OPINION: As a single agent, vincristine is associated with brief and incomplete responses, but in combination with other agents, vincristine has dramatically improved the outcomes of lymphoid malignancies such as ALL. Vincristine is a key drug of hyper-fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone, an intensive chemotherapeutic regimen for the treatment of ALL, and of cyclophosphamid, adriamycin, vincristine and prednisone, which has been used extensively in the treatment of patients with aggressive or indolent lymphomas and Richter syndrome. The strong antileukemic activity of vincristine has been limited by its variable and unpredictable pharmacological characteristics, narrow therapeutic index and neurotoxicity profile. These characteristics prompted the development of liposomal vincristine, which has optimized its clinical application. Liposomal vincristine has promising antileukemic activity, and it is approved by the FDA as a single agent for the treatment of relapsed/refractory Philadelphia chromosome-negative ALL.

Phase I study of BIIB028, a selective heat shock protein 90 inhibitor, in patients with refractory metastatic or locally advanced solid tumors.

PURPOSE: Heat shot protein 90 (Hsp90) is a ubiquitous molecular chaperone involved in protein folding, activation, and assembly, including key mediators of signal transduction, cell-cycle control, and transcriptional regulation. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of BIIB028, a prodrug designed to inhibit Hsp90 activity. EXPERIMENTAL DESIGN: Patients with advanced solid tumors were enrolled and received escalating doses of BIIB028 intravenously twice a week in 21-day cycles (3+3 design). Response was evaluated after two cycles. RESULTS: Forty-one patients received doses of 6 to 192 mg/m2. The maximum tolerated dose was 144 mg/m2. Dose-limiting toxicities were syncope (n=1) and fatigue (n=1). Common toxicities at least possibly related to drug were grades 1 to 2, including fatigue (46%), diarrhea (44%), nausea (44%), vomiting (29%), hot flushes (29%), and abnormal dreams (17%). The concentration-time curves for day 1 and day 18 for both prodrug and active metabolite (CF2772) showed a negligible difference. There was a dose-dependent increase in plasma exposure for BIIB028 (CF3647) and CF2772 with plasma half-life of 0.5 and 2.1 hours, respectively. Pharmacodynamic analyses showed significant increases in Hsp70 in peripheral blood mononuclear cells and significantly decreased circulating human EGF receptor-2 extracellular domain in all patients who received BIIB028 at dose levels of 48 mg/m2 or more. Stable disease for at least eight cycles (24 weeks) was achieved in 5 (12%) patients (for durations of 6, 6, 8, 12.5, and 19 months). CONCLUSION: BIIB028 is a well-tolerated molecule that showed target impact and was associated with prolonged stable disease in two patients.