Dose-escalation trial of combination dabrafenib, trametinib, and AT13387 in patients with BRAF-mutant solid tumors.

BACKGROUND: Combination BRAF and MEK inhibitor therapy is an active regimen in patients who have BRAF V600E-mutated tumors; however, the clinical efficacy of this therapy is limited by resistance. Preclinically, the addition of heat shock protein 90 (HSP90) inhibition improves the efficacy of BRAF inhibitor therapy in both BRAF inhibitor-sensitive and BRAF inhibitor-resistant mutant cell lines. METHODS: Cancer Therapy Evaluation Program study 9557 (ClinicalTrials.gov identifier NCT02097225) is a phase 1 study that was designed to assess the safety and efficacy of the small-molecule HSP90 inhibitor, AT13387, in combination with dabrafenib and trametinib in BRAF V600E/K-mutant solid tumors. Correlative analyses evaluated the expression of HSP90 client proteins and chaperones. RESULTS: Twenty-two patients with metastatic, BRAF V600E-mutant solid tumors were enrolled using a 3 + 3 design at four dose levels, and 21 patients were evaluable for efficacy assessment. The most common tumor type was colorectal cancer (N = 12). Dose-limiting toxicities occurred in one patient at dose level 3 and in one patient at dose level 4; specifically, myelosuppression and fatigue, respectively. The maximum tolerated dose was oral dabafenib 150 mg twice daily, oral trametinib 2 mg once daily, and intravenous AT13387 260 mg/m2 on days 1, 8, and 15. The best response was a partial response in two patients and stable disease in eight patients, with an overall response rate of 9.5% (90% exact confidence interval [CI], 2%-27%), a disease control rate of 47.6% (90% CI, 29%-67%), and a median overall survival of 5.1 months (90% CI, 3.4-7.6 months). There were no consistent proteomic changes associated with response or resistance, although responders did have reductions in BRAF expression, and epidermal growth factor receptor downregulation using HSP90 inhibition was observed in one patient who had colorectal cancer. CONCLUSIONS: HSP90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of modest disease control in a heavily pretreated population. Additional translational work may identify tumor types and resistance mechanisms that are most sensitive to this approach.

Clinical Outcome Assessments Toolbox for Radiopharmaceuticals.

For nearly 40 years, the U.S. National Cancer Institute (NCI) has funded health-related quality-of-life (HRQOL) and symptom management in oncology clinical trials as a method for including a cancer patient's experience during and after treatment. The NCI's planned scope for HRQOL, symptom and patient-reported outcomes management research is explained as it pertains to radiopharmaceutical clinical development. An effort already underway to support protocol authoring via an NCI Cancer Therapy Evaluation Program (CTEP) Centralized Protocol Writing Service (CPWS) is described as this service aids incorporation of HRQOL, symptom and patient-reported outcomes management research into sponsored protocols.

Leveraging National Cancer Institute Programmatic Collaboration for Single Radiopharmaceutical Drug Master Files.

Targeted radiopharmaceutical conjugates intended for therapeutic use often are made of three key components, a decaying radionuclide, a chemical chelator/linker, and a targeted molecular entity. The National Cancer Institute (NCI) Experimental Therapeutics Program has accepted four radiopharmaceutical drug products so far that fit the targeted radiopharmaceutical conjugate class. As the NCI sharpens its thinking about its role as an investigational new drug sponsor for radiopharmaceuticals in clinical development, it has considered the relative merits of modular radiopharmaceutical drug master files. Here, the NCI provides its perspective on modular radiopharmaceutical drug master files as it initiates a clinical development program for such agents and further organizes its radiopharmaceutical Small Business Innovation Research portfolio.

Radiopharmaceuticals for Persistent or Recurrent Uterine Cervix Cancer.

Uterine cervix cancers pose therapeutic challenges because of an overactive ribonucleotide reductase, which provides on-demand deoxyribonucleotides for DNA replication or for a DNA damage repair response. Ribonucleotide reductase overactivity bestows cancer cell resistance to the effects of radiotherapy and chemotherapy used to treat disease; but nevertheless, this same biologic overexpression provides opportune vulnerabilities relatively specific to uterine cervix cancers for new therapeutic strategies to take advantage. The discovery of human epidermal growth factor receptor 2 (ErbB2 or HER2) overexpression on metastatic uterine cervix cancer cells provides an opportunity for clinical trials of targeted radiopharmaceuticals in combination with DNA damage response modifying drugs. The National Cancer Institute's clinical trial infrastructure and its experimental therapeutics portfolio can now offer clinical trial evaluation of molecularly-targeted and tolerated radiopharmaceutical-drug combinations for women with persistent or recurrent metastatic uterine cervix cancer. This article discusses the current thinking of the National Cancer Institute in regard to attractive radiopharmaceutical strategies for this disease and others.

Radiopharmaceuticals for Relapsed or Refractory Ovarian Cancers.

Targeted radiopharmaceuticals for therapeutic use deliver radionuclides directly to tumor anywhere in the body, and therefore, have renewed interest for clinical development in women with disseminated chemorefractory ovarian cancers. About two in every five women with advanced stage ovarian cancer outlive their disease after the first treatment phase, with the rest rendered incurable due to the chemorefractory nature of their disease. The National Cancer Institute (NCI) Cancer Therapy Evaluation Program conducted 67 phase I or phase Ib trials among women with relapsed or refractory ovarian cancer between 1989 and 2017 in an effort to uncover tolerable and effective drug combinations intended to increase survival rates. None of these early clinical development phase trials involved radiopharmaceuticals. Here, the NCI provides its perspective on targeted radiopharmaceutical conjugates alone or in combination with its experimental therapeutics portfolio for women with relapsed or refractory ovarian cancer. An infrastructure build for Federal radiopharmaceutical medical monitoring and adverse event reporting has begun.

Radiopharmaceuticals for Relapsed or Refractory Leukemias.

Radiopharmaceuticals, meaning drugs that hold a radionuclide intended for use in cancer patients for treatment of their disease or for palliation of their disease-related symptoms, have gained new interest for clinical development in adult patients with relapsed or refractory leukemia. About one-third of adult patients outlive their leukemia, with the remainder unable to attain complete remission status following the first phase of treatment due to refractory bone marrow or blood residual microscopic disease. The National Cancer Institute (NCI) Cancer Therapy Evaluation Program conducted 49 phase 1-1b trials in adult patients with leukemia between 1986 and 2017 in an effort to discover tolerated and effective therapeutic drug combinations intended to improve remission and mortality rates. None of these trials involved radiopharmaceuticals. In this article, the NCI perspective on the challenges encountered in and on the future potential of radiopharmaceuticals alone or in combination for adult patients with relapsed or refractory leukemia is discussed. An effort is underway already to build-up the NCI's clinical trial enterprise infrastructure for radiopharmaceutical clinical development.

Phase I Trial of Triapine-Cisplatin-Paclitaxel Chemotherapy for Advanced Stage or Metastatic Solid Tumor Cancers.

Ribonucleotide reductase (RNR) is an enzyme involved in the de novo synthesis of deoxyribonucleotides, which are critical for DNA replication and DNA repair. Triapine is a small-molecule RNR inhibitor. A phase I trial studied the safety of triapine in combination with cisplatin-paclitaxel in patients with advanced stage or metastatic solid tumor cancers in an effort to capitalize on disrupted DNA damage repair. A total of 13 patients with various previously treated cancers were given a 96-h continuous intravenous (i.v.) infusion of triapine (40-120 mg/m2) on day 1, and then 3-h i.v. paclitaxel (80 mg/m2) followed by 1-h i.v. cisplatin (50-75 mg/m2) on day 3. This combination regimen was repeated every 21 days. The maximum tolerated dose (MTD) for each agent was identified to be triapine (80 mg/m2), cisplatin (50 mg/m2), and paclitaxel (80 mg/m2). Common grade 3 or 4 toxicities included reversible anemia, leukopenia, thrombocytopenia, or electrolyte abnormalities. The combination regimen of triapine-cisplatin-paclitaxel resulted in no objective responses; however, five (83%) of six patients treated at the MTD had stable disease between 1 and 8 months duration. This phase I study showed that the combination regimen of triapine-cisplatin-paclitaxel was safe and provides a rational basis for a follow-up phase II trial to evaluate efficacy and progression-free survival in women with metastatic or recurrent uterine cervix cancer.

A phase 1/pharmacokinetic study of sunitinib in combination with highly active antiretroviral therapy in human immunodeficiency virus-positive patients with cancer: AIDS Malignancy Consortium trial AMC 061.

BACKGROUND: The treatment of non-acquired immunodeficiency syndrome-defining cancers may be complicated by drug interactions between highly active antiretroviral therapy (HAART) and chemotherapy. This trial is the first by the AIDS Malignancy Consortium to assess targeted therapies and HAART in human immunodeficiency virus-positive patients (ClinicalTrials.gov identifier: NCT00890747). METHODS: In a modified phase 1 study of sunitinib, patients were stratified into 2 treatment arms based on whether they were receiving therapy with ritonavir, a potent CYP3A4 inhibitor. Patients in treatment arm 1 (non-ritonavir HAART) received standard sunitinib dosing (50 mg/day). Treatment arm 2 (ritonavir-based HAART) used a phase 1, 3 + 3 dose escalation design (from 25 mg/day to 50 mg/day). Cycles were comprised of 4 weeks on treatment followed by a 2-week break (6 weeks total). The pharmacokinetics of sunitinib and its active metabolite (N-desethyl sunitinib) were assessed. RESULTS: Nineteen patients were enrolled and were evaluable. Patients on treatment arm 1 tolerated treatment with no dose-limiting toxicity observed. In treatment arm 2, a dose-limiting toxicity was experienced at a dose of 37.5 mg, and an additional 3 of 5 patients experienced grade 3 neutropenia (toxicity graded as per National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]), an uncommon toxicity of sunitinib. No patient achieved a response, but 10 patients had stable disease, including 8 with prolonged disease stability. Efavirenz, a potent inducer of CYP3A4, resulted in increased exposure of N-desethyl sunitinib, whereas ritonavir caused decreased exposure of the metabolite. Hand-foot syndrome was associated with higher steady-state trough concentrations of sunitinib. CONCLUSIONS: Patients receiving non-ritonavir-based HAART regimens tolerated standard dosing of sunitinib. Patients receiving ritonavir-based therapy who were treated with a dose of 37.5 mg/day experienced higher toxicities. Dose reductions of sunitinib to 37.5 mg may be warranted in patients receiving ritonavir.

Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study.

BACKGROUND: Chemotherapy has historically proven ineffective in advanced differentiated thyroid cancers, but the realisation that various tyrosine kinases are activated in the disease suggested a potential therapeutic role for tyrosine-kinase inhibitors. We investigated the safety and efficacy of pazopanib. METHODS: This phase 2 trial was done from Feb 22, 2008, to Jan 31, 2009, in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers. Each patient received 800 mg continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred. Up to two previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrolment was a requirement for inclusion. The primary endpoint was any tumour response, according to the Response Evaluation Criteria in Solid Tumors 1.0. This study is registered with ClinicalTrials.gov, number NCT00625846. FINDINGS: 39 patients were enrolled. One patient had received no previous radioiodine therapy and another withdrew consent before treatment. Clinical outcomes could, therefore, be assessed in 37 patients (19 [51%] men, median age 63 years). The study is closed to accrual of new patients, but several enrolled patients are still being treated. Patients received a median of 12 cycles (range 1 to >23, total >383). Confirmed partial responses were recorded in 18 patients (response rate 49%, 95% CI 35-68), with likelihood of response lasting longer than 1 year calculated to be 66%. Maximum concentration of pazopanib in plasma during cycle one was significantly correlated with radiographic response (r=-0·40, p=0·021). 16 (43%) patients required dose reductions owing to adverse events, the most frequent of which (any grade) were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhoea (27), and nausea (27). Two patients who died during treatment had pre-existing contributory disorders. INTERPRETATION: Pazopanib seems to represent a promising therapeutic option for patients with advanced differentiated thyroid cancers. The correlation of the patient's response and pazopanib concentration during the first cycle might indicate that treatment can be individualised to achieve optimum outcomes. Assessment of pazopanib in an expanded cohort of patients with differentiated thyroid cancer, as well as in cohorts of patients with medullary and anaplastic thyroid cancers, is presently being done. FUNDING: National Cancer Institute, supported in part by NCI CA15083 and CM62205.