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Purpose: Indoximod is an oral inhibitor of the indoleamine 2,3-dioxygenase pathway, which causes tumor-mediated immunosuppression. Primary endpoints were maximum tolerated dose (MTD) and toxicity for indoximod in patients with advanced solid tumors. Secondary endpoints included response rates, pharmacokinetics, and immune correlates., Experimental Design: Our 3+3 phase I trial comprised 10 dose levels (200, 300, 400, 600, and 800 mg once/day; 600, 800, 1200, 1600, and 2000 mg twice/day). Inclusion criteria were measurable metastatic solid malignancy, age ≥18 years, and adequate organ/marrow function. Exclusion criteria were chemotherapy ≤ 3 weeks prior, untreated brain metastases, autoimmune disease, or malabsorption., Results: In 48 patients, MTD was not reached at 2000 mg twice/day. At 200 mg once/day, 3 patients previously treated with checkpoint inhibitors developed hypophysitis. Five patients showed stable disease >6 months. Indoximod plasma AUC and Cmax plateaued above 1200mg. Cmax (~12 μM at 2000 mg twice/day) occurred at 2.9 hours, and half-life was 10.5 hours. C reactive protein (CRP) levels increased across multiple dose levels., Conclusions: Indoximod was safe at doses up to 2000 mg orally twice/day. Best response was stable disease >6 months in 5 patients. Induction of hypophysitis, increased tumor antigen autoantibodies and CRP levels were observed., Competing Interests: Charles Link, Nicholas Vahanian, W. Jay Ramsey, and Mario Mautino all have ownership/employment relationships with NewLink Genetics Inc., which is developing indoximod. Hatem Soliman is the lead investigator on a phase 2 clinical trial sponsored by NewLink Genetics.

Background: MK-5108 is a potent/highly selective Aurora A kinase inhibitor., Methods: A randomized Phase I study of MK-5108, administered p.o. BID Q12h on days 1-2 in 14-21 day cycles either alone (MT; Panel1/n = 18; 200 to 1800 mg) or in combination (CT; Panel2/n = 17; 100 to 225 mg) with IV docetaxel 60 mg/m(2), determined the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (Panel1, only) and tumor response in patients with advanced solid tumors. This study was terminated early due to toxicities in Panel2 at MK-5108 doses below the anticipated PK exposure target., Results: 35 patients enrolled (33 evaluable for tumor response). No dose-limiting toxicities (DLTs) were observed in Panel1; three patients had 3 DLTs in Panel2 (G3 and G4 febrile neutropenia at 200 and 450 mg/day, respectively; G3 infection at 450 mg/day). In Panel1, AUC0-12hr and Cmax increased less than dose proportionally following the first MT dose but increased roughly dose proportionally across 200 to 3600 mg/day after 4th dose. The t1/2 ranged from 6.6 to 13.5 h across both panels. No clear effects on immunohistochemistry markers were observed; however, significant dose-related increases in gene expression were seen pre-/post-treatment. Best responses were 9/17 stable disease (SD) (Panel1) as well as 1/16 PR and 7/16 SD (Panel2) (450 mg/day)., Conclusions: MK-5108 MT was well tolerated at doses up to 3600 mg/day with plasma levels exceeding the minimum daily exposure target (83 μM*hr). The MTD for MK-5108 + docetaxel (CT) was established at 300 mg/day, below the exposure target. Use of pharmacodynamic gene expression assays to determine target engagement was validated.

The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach., (©2015 American Association for Cancer Research.)

Many cancers adapt to chemotherapeutic agents by upregulating membrane efflux pumps that export drugs from the cytoplasm, but this response comes at an energetic cost. In breast cancer patients, expression of these pumps is low in tumors before therapy but increases after treatment. While the evolution of therapeutic resistance is virtually inevitable, proliferation of resistant clones is not, suggesting strategies of adaptive therapy. Chemoresistant cells must consume excess resources to maintain resistance mechanisms, so adaptive therapy strategies explicitly aim to maintain a stable population of therapy-sensitive cells to suppress growth of resistant phenotypes through intratumoral competition. We used computational models parameterized by in vitro experiments to illustrate the efficacy of such approaches. Here, we show that low doses of verapamil and 2-deoxyglucose, to accentuate the cost of resistance and to decrease energy production, respectively, could suppress the proliferation of drug-resistant clones in vivo. Compared with standard high-dose-density treatment, the novel treatment we developed achieved a 2-fold to 10-fold increase in time to progression in tumor models. Our findings challenge the existing flawed paradigm of maximum dose treatment, a strategy that inevitably produces drug resistance that can be avoided by the adaptive therapy strategies we describe.

Purpose: Chemotherapy-induced amenorrhea is a serious concern for women undergoing cancer therapy. This prospective randomized trial evaluated the use of gonadotropin-releasing hormone (GnRH) analog triptorelin to preserve ovarian function in women treated with chemotherapy for early-stage breast cancer., Patients and Methods: Premenopausal women age 44 years or younger were randomly assigned to receive either triptorelin or no triptorelin during (neo)adjuvant chemotherapy and were further stratified by age (< 35, 35 to 39, > 39 years), estrogen receptor status, and chemotherapy regimen. Objectives included the resumption of menses and serial monitoring of follicle-stimulating hormone (FSH) and inhibin A and B levels., Results: Targeted for 124 patients with a planned 5-year follow-up, the trial was stopped for futility after 49 patients were enrolled (median age, 39 years; range, 21 to 43 years); 47 patients were treated according to assigned groups with four cycles of adriamycin plus cyclophosphamide alone or followed by four cycles of paclitaxel or six cycles of fluorouracil, epirubicin, and cyclophosphamide. Menstruation resumed in 19 (90%) of 21 patients in the control group and in 23 (88%) of 26 in the triptorelin group (P= .36). Menses returned after a median of 5.8 months (range, 1 to 19 months) after completion of chemotherapy in the triptorelin versus 5.0 months (range, 0 to 28 months) in the control arm (P= .58). Two patients (age 26 and 35 years at random assignment) in the control group had spontaneous pregnancies with term deliveries. FSH and inhibin B levels correlated with menstrual status., Conclusion: When stratified for age, estrogen receptor status, and treatment regimen, amenorrhea rates on triptorelin were comparable to those seen in the control group.

Background: Histone deacetylases (HDACs) are crucial components of the oestrogen receptor (ER) transcriptional complex. Preclinically, HDAC inhibitors can reverse tamoxifen/aromatase inhibitor resistance in hormone receptor-positive breast cancer. This concept was examined in a phase II combination trial with correlative end points., Methods: Patients with ER-positive metastatic breast cancer progressing on endocrine therapy were treated with 400 mg of vorinostat daily for 3 of 4 weeks and 20 mg tamoxifen daily, continuously. Histone acetylation and HDAC2 expression in peripheral blood mononuclear cells were also evaluated., Results: In all, 43 patients (median age 56 years (31-71)) were treated, 25 (58%) received prior adjuvant tamoxifen, 29 (67%) failed one prior chemotherapy regimen, 42 (98%) progressed after one, and 23 (54%) after two aromatase inhibitors. The objective response rate by Response Evaluation Criteria in Solid Tumours criteria was 19% and the clinical benefit rate (response or stable disease >24 weeks) was 40%. The median response duration was 10.3 months (confidence interval: 8.1-12.4). Histone hyperacetylation and higher baseline HDAC2 levels correlated with response., Conclusion: The combination of vorinostat and tamoxifen is well tolerated and exhibits encouraging activity in reversing hormone resistance. Correlative studies suggest that HDAC2 expression is a predictive marker and histone hyperacetylation is a useful pharmacodynamic marker for the efficacy of this combination.

Introduction: A multicenter, open-label phase III study was conducted to test whether sunitinib plus paclitaxel prolongs progression-free survival (PFS) compared with bevacizumab plus paclitaxel as first-line treatment for patients with HER2(-) advanced breast cancer., Patients and Methods: Patients with HER2(-) advanced breast cancer who were disease free for ≥ 12 months after adjuvant taxane treatment were randomized (1:1; planned enrollment 740 patients) to receive intravenous (I.V.) paclitaxel 90 mg/m(2) every week for 3 weeks in 4-week cycles plus either sunitinib 25 to 37.5 mg every day or bevacizumab 10 mg/kg I.V. every 2 weeks. [corrected], Results: The trial was terminated early because of futility in reaching the primary endpoint as determined by the independent data monitoring committee during an interim futility analysis. At data cutoff, 242 patients had been randomized to sunitinib-paclitaxel and 243 patients to bevacizumab-paclitaxel. Median PFS was shorter with sunitinib-paclitaxel (7.4 vs. 9.2 months; hazard ratio [HR] 1.63 [95% confidence interval (CI), 1.18-2.25]; 1-sided P = .999). At a median follow-up of 8.1 months, with 79% of sunitinib-paclitaxel and 87% of bevacizumab-paclitaxel patients alive, overall survival analysis favored bevacizumab-paclitaxel (HR 1.82 [95% CI, 1.16-2.86]; 1-sided P = .996). The objective response rate was 32% in both arms, but median duration of response was shorter with sunitinib-paclitaxel (6.3 vs. 14.8 months). Bevacizumab-paclitaxel was better tolerated than sunitinib-paclitaxel. This was primarily due to a high frequency of grade 3/4, treatment-related neutropenia with sunitinib-paclitaxel (52%) precluding delivery of the prescribed doses of both drugs., Conclusion: The sunitinib-paclitaxel regimen evaluated in this study was clinically inferior to the bevacizumab-paclitaxel regimen and is not a recommended treatment option for patients with advanced breast cancer., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To test the tolerability, safety, and recommended phase II dose of CP-724,714, a reversible, highly selective, oral HER2 tyrosine kinase inhibitor in patients with advanced solid tumor malignancies that express HER2., Experimental Design: A phase I trial evaluated escalating doses of CP-724,714, administered daily in 21-day cycles. Pharmacokinetics/pharmacodynamics were evaluated in serial blood samples and in pretreatment and posttreatment tumor and skin biopsies., Results: Thirty female patients [median age, 51 years (range, 37-71); median performance status, 1 (range, 0-1)] received CP-724,714 at four dose levels: 250 mg once daily (4 patients), 250 mg twice daily (15 patients), 250 mg thrice daily (6 patients), and 400 mg twice daily (5 patients). Dosing at 400 mg twice daily and 250 mg thrice daily was not feasible due to reversible, cholestatic liver dysfunction. Treatment-related adverse events were nausea (58%), asthenia (23%), hyperbilirubinemia (27%), elevated transaminases (30%), and skin rash (30%); neither diarrhea nor cardiomyopathy was observed. No objective responses were observed in 28 evaluable patients; 8 (29%) patients had stable disease. Twenty-seven (96%) patients received prior trastuzumab and were heavily pretreated (median prior chemotherapy, 6; range, 1-11). Systemic exposure exceeded the in vivo efficacy threshold required in preclinical studies., Conclusions: Dose-limiting toxicities included hyperbilirubinemia, elevated alanine aminotransferase, thrombocytopenia and pulmonary embolus. Although the protocol-specified maximum tolerated dose of CP-724,714 was 250 mg thrice daily, the recommended phase II dose was 250 mg twice daily due to excessive late-cycle hepatotoxicity. Despite extensive prior treatment, 29% of patients had stable disease. A phase II trial has been initiated in patients with breast cancer.

Background: The majority of women diagnosed with early-stage breast cancer have an excellent long-term prognosis, but many will undergo temporary or permanent chemotherapy-induced amenorrhea., Methods: While breast cancer is more common in older women, about 1 in 200 women under the age of 40 is at risk to develop breast cancer. Many of these women benefit from chemotherapy but are afraid to risk the opportunity to bear children. The authors review the current studies on the impact of adjuvant chemotherapy on amenorrhea and fertility in women with breast cancer., Results: The likelihood of amenorrhea is based on the specific adjuvant chemotherapy regimen administered and the age of the patient. Future childbirth is a viable option for women treated for breast cancer at an early stage. While the use of tamoxifen as a hormonal therapy in premenopausal breast cancer is now the standard of care, no conclusive data confirm the benefit of GnRH agonists in adjuvant therapy after treatment with chemotherapy followed by tamoxifen., Conclusions: As more women over the age of 35 consider pregnancy, fertility issues are becoming important areas of investigation for the adjuvant treatment of breast cancer. Whether chemotherapy-induced amenorrhea has a prognostic effect remains unclear, and further studies are warranted.

Age is the most important risk factor for the development of breast cancer. The risk of breast cancer continues to increase in American women until the age of 80 years. A family history of breast cancer helps identify those who possibly have the highest risk of developing breast cancer; however, most women who develop breast cancer do not have a first-degree relative with a history of breast cancer. Currently, the Gail model is a commonly used model to identify risk, and this model has now been validated in several populations of women undergoing screening for breast cancer. The first large-scale breast cancer prevention trial investigating the preventive effects of tamoxifen has demonstrated a decrease in the development of breast cancer by almost 50% in the women in the tamoxifen treatment arm as compared with those receiving placebo. The NSABP P-1 trial was the largest of the three tamoxifen breast cancer prevention trials and had the greatest power to detect a difference between the two treatment groups in breast cancer events. This trial also included the largest percentage of postmenopausal women. It is unclear why the Italian and Royal Marsden Hospital trials had negative results regarding the preventive effects of tamoxifen. These two trials were strikingly different from the NSABP P-1 trial, however, and they included a different population of women. The issues surrounding the use of HRT for treatment of hot flashes in the Italian and Royal Marsden Hospital trials adds to the controversy concerning the negative results of these trials. The new SERM, raloxifene, has shown promise in preliminary studies as a preventive agent for breast cancer. The STAR trial will open soon and will evaluate the efficacy of raloxifene in preventing breast cancer in a prospective fashion, comparing its efficacy with tamoxifen treatment. Other endpoints will evaluate side effects such as menopausal symptoms, endometrial cancer, thromboembolic events, and benefits regarding serum lipids and incidence of osteoporotic bone fractures. The development of SERMs results from an understanding of novel mechanisms of ER modulation and allows targeting for favorable effects in specific tissues. The challenge is to develop an ideal SERM that is effective in preventing breast cancer and does not increase the risk of endometrial cancer, while providing beneficial estrogenic effects on serum lipids and bone mineral density changes. Estrogen receptor-mediated intracellular processes are complex. There are at least two different types of estrogen receptors. The alpha receptors predominate in the breast and uterus, and the beta receptors predominate in the bone and blood vessels. Many proteins also interact with these receptors as co-activators or co-repressors. Transcription-activating factors modulate the effects of estrogen on its target genes. Future prevention strategies may use a combined targeted approach to inhibit ER-mediated cancer progression pathways. The retinoids are under investigation in prevention studies for a multitude of cancers, because they have been shown to inhibit cellular proliferation and to induce cellular differentiation. The retinoid 4HPR was selected for use in breast cancer prevention studies because of its low toxicity profile and prevention efficacy in preclinical studies. It is now being used in combination with tamoxifin in a phase II breast cancer prevention trial. Multiple surrogate endpoint biomarkers are being measured before and after treatment, including measurement of serum IGF-I levels. Future directions in breast cancer prevention include the development of more potent hormonal therapies that completely inhibit ER-mediated cancer progression and, ultimately, multitargeted therapies involving agents that work synergistically.

BACKGROUND: There has been an explosion in the development of hormonal therapies for the treatment of breast cancer. Several new agents have been approved for the treatment of breast cancer in the metastatic setting, and trials are ongoing in the adjuvant and prevention setting to improve hormonal therapy for the prevention and treatment of breast cancer. METHODS: The literature on new hormonal therapies for the treatment of breast cancer is reviewed, with an emphasis on newer agents. RESULTS: Two antiestrogens are now approved in the United States for the treatment of metastatic breast cancer. Other antiestrogens have activity in metastatic breast cancer as well as in osteoporosis. Newer pure antiestrogens may overcome resistance to tamoxifen. Several aromatase inhibitors are available for the treatment of metastatic breast cancer. CONCLUSIONS: Many hormonal agents are now available for both adjuvant and advanced disease settings. Developments will depend on clarifying mechanisms of resistance to antiestrogens and identifying new classes of agents that lack cross-resistance to standard therapy.

Germline mutations in the PTEN gene have recently been identified in some individuals with Cowden disease (CD), Lhermitte-Duclos disease (LDD), and Bannayan-Zonana syndrome. We report on a patient with CD and LDD in whom a unique de novo germline missense mutation is present in the PTEN gene. Direct sequence analysis detected a transitional change (T-->C) at nucleotide 335, resulting in substitution of the amino acid proline for leucine. The mutation is in exon 5, which has been proposed as a "hot-spot" for germline mutations. Comparison of this patient's clinical course with the previously reported cases of CD and LDD shows more extensive and more severe clinical findings than reported previously. Findings in this patient contribute to the current understanding of germline PTEN mutations and clinical outcome.