Phase II Trial Of Neoadjuvant Bevacizumab With Modified FOLFOX7 In Patients With Stage II And III Rectal Cancer
PRIMARY OBJECTIVES:
I. To determine if six cycles of modified fluorouracil, leucovorin calcium, and oxaliplatin
(mFOLFOX7) plus bevacizumab (Avastin) will yield complete pathologic response (cPR) of 25% or
more in the primary tumor of patients with stage II and III rectal cancer.
SECONDARY OBJECTIVES:
I. To assess the rate of tumor regression (pathologic stage lower than clinical stage) after
6 cycles of mFOLFOX7 and bevacizumab in the primary rectal cancer.
II. To assess local recurrence rate over 3 years after 6 cycles of mFOLFOX7 and bevacizumab.
TERTIARY OBJECTIVES:
I. Correlation of the following marker with response (defined as CPR or down staging):
- Intratumoral Gene expression and germline polymorphism of genes involved in the vascular
endothelial growth factor (VEGF) and VEGF independent pathways (VEGF, vascular
endothelial growth factor receptor 1 [VEGFR1], VEGFR2, interleukin-8 [IL8], chemokine
(C-X-C motif) receptor 2 [CXCR2], intercellular adhesion molecule [ICAM], VEGFR1 and
VEGFR2, neuropilin 1 or 2 [NRP1,2], cluster of differentiation [CD] 44, aldehyde
dehydrogenase [ALDH], leucine-rich repeats and immunoglobulin-like [LRIG].
- Circulating tumor cells (CTC) and VEGF-factor A (A) on the CTC.
II. Prediction of surgical resection margin by pretreatment magnetic resonance imaging (MRI).
OUTLINE:
Patients receive bevacizumab intravenously (IV) over 30-90 minutes, oxaliplatin IV over 2
hours, leucovorin calcium IV, and fluorouracil IV continuously over 46-48 hours on day 1.
Treatment repeats every 14 days for 6 courses in the absence of disease progression or
unacceptable toxicity. Within 6-8 weeks after treatment, patients undergo surgery.
After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.
A Phase 1/2, Open-Label, Safety, Pharmacokinetic and Preliminary Efficacy Study of Oral Rociletinib in Patients With Previously Treated Mutant EGFR Non-Small Cell Lung Cancer (NSCLC)
Lung cancer remains the most common cancer worldwide with non-small cell lung cancer
accounting for 85% of cases. Cytotoxic chemotherapy has been the mainstay of patients with
NSCLC; however, survival rates remain low and toxicity is significant. Molecularly targeted
therapies have proven to be superior to chemotherapy for NSCLC patients whose tumors have
mutations in EGFR. Recent studies have established tyrosine kinase inhibitors (TKIs) as the
gold standard for treating EGFR-mutation-positive NCSLC. However, patients on TKIs
eventually progress, and in approximately 50% of cases, progression is due to development of
an additional mutation called T790M. There are currently no approved therapies for patients
who progress on TKIs. Rociletinib may provide an effective therapy for a patient population
with few alternative treatment options. Nonclinical data demonstrate that rociletinib
inhibits T790M. It is anticipated that rociletinib may promote cell death in tumor cells
with the T790M mutation, thus providing possible therapeutic benefit in patients who have
developed T790M-mediated resistance to first generation TKIs.
This is a two-part, open-label study of oral rociletinib administered daily in previously
treated NSCLC patients who have documented evidence of an activating mutation in the EGFR
gene and have failed treatment with an EGFR inhibitor such as erlotinib, gefitinib or
afatinib.
This study will include 2 parts:
Phase 1 (completed enrolment): Dose-escalation Period with 21-day cycles; optional Treatment
Extension Period starting on Day 22
Phase 2 (currently enrolling): Evaluation of activity and safety in patients with the T790M
EGFR mutation who have:
Cohort A - Progressed on EGFR directed therapy (irrespective of the number and order of
previous lines of NSCLC therapy) or Cohort B - Progression on the first single agent EGFR
directed therapy received and also had no more than one previous line of chemotherapy
A Randomized Phase 2, Double-blind, Placebo-controlled, Treat-to-Target, Parallel-group,
3-arm, Multicenter Study to Assess the Efficacy and Safety of Canagliflozin as Add-on
Therapy to Insulin in the Treatment of Subjects with Type 1 Diabetes Mellitus
Canagliflozin (CANA) is an oral antihyperglycemic agent (AHA) approved for the treatment of subjects with Type 2 Diabetes Mellitus (T2DM). In subjects with T2DM, CANA lowers blood glucose by an insulin-independent mechanism and has an intrinsic low risk of hypoglycemia. In subjects with T1DM the addition of CANA to intensive insulin therapy is expected to lead to less insulin requirement which is expected to lead to a reduced insulin dose requirement, weight gain, glucose variability and low the risk of hypoglycemia. The primary objective of this study is to assess the effect of CANA 100 mg and 300 mg compared with placebo on the change in HbA1c and body weight after 18 weeks of treatment. This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, interventional study of CANA in male and female subjects between the ages of 25 years to 65 years, inclusive, with a diagnosis of T1DM for at least 1 year, and inadequate glycemic control (ie, HbA1c of 7.0% to 9.0%) on basal plus bolus insulin at screening. Approximately 330 subjects will be randomly assigned in this study (20 at the USC site), with approximately 110 subjects randomized per treatment group. The primary hypothesis will be assessed using a composite primary endpoint: proportion of subjects with HbA1c reduction 0.4% and no increase in body weight. Assuming the proportion of subjects meeting the composite criteria is 20% for placebo and 40% for each CANA dose, and assuming a 2-sided family-wise Type I error rate of 0.05, it is estimated that a sample size of 100 randomized subjects per group will be required to achieve 84% power for the comparison of each CANA dose to placebo. A modestly larger sample size (110 subjects per arm) will be randomized to each treatment arm. The modified intent-to-treat (mITT) analysis set includes all randomized subjects who have received at least 1 dose of double-blind study medication. The per-protocol (PP) analysis set consists of all mITT subjects who complete the 18-week double-blind treatment phase, and have no major protocol deviations that may affect the interpretation of the primary efficacy endpoint. The completers analysis set consists of all mITT subjects who complete the 18-week double blind treatment period. The primary efficacy endpoint will be proportion of subjects with HbA1c reduction 0.4% and no increase in body weight after 18 weeks of treatment. The primary efficacy endpoint will be analyzed longitudinally using a generalized linear mixed model. The model will include the fixed, categorical effects of treatment, stratification factor (use of CSII vs MDI), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline HbA1c, baseline body weight, and baseline-by-visit interactions. An unstructured covariance will be used to model the within-patient errors. The odds ratio and 2-sided 95% confidence interval (CI) for the treatment comparison at Week 18 (CANA vs placebo) will be estimated based on this model. As a sensitivity analysis, the last-observation-carried-forward method will be applied when the Week 18 values are missing. The odds ratio will be assessed by a logistic regression model with terms for baseline HbA1c, baseline body weight, treatment and stratification factor.
A Prospective, Non-randomized, Concurrent Control, Open Label, Post-approval Study of NovoTTF-100A in Recurrent GBM Patient
PAST CLINICAL EXPERIENCE:
The effect of the electric fields generated by the NovoTTF-100A device (TTFields, TTF) has
been tested in a large prospective, randomized trial, in 237 recurrent GBM patients. The
outcome of subjects treated with the NovoTTF-100A device was compared to those treated with
an effective best standard of care chemotherapy (including bevacizumab). NovoTTF-100A
subjects had comparable overall survival to subjects receiving the best available
chemotherapy in the US today. Similar results showing comparability of NovoTTF-100A to BSC
chemotherapy were seen in all secondary endpoints.
Recurrent GBM patients treated with the NovoTTF-100A device in this trial experienced fewer
side effects in general, significantly fewer treatment related side effects, and
significantly lower gastrointestinal, hematological and infectious adverse events compared to
controls. The only device-related adverse events seen were a mild to moderate skin irritation
beneath the device electrodes. Finally, quality of life measures were better in NovoTTF-100A
subjects as a group when compared to subjects receiving effective best standard of care
chemotherapy.
DESCRIPTION OF THE TRIAL:
Patients with GBM whose disease has first recurred despite standard treatment (Surgery,
radiation therapy, Temozolomide treatment) and meet all of the requirements for participation
in the study will be recruited to one of two groups based on patient preference alone:
1. Treatment with the NovoTTF-100A device, or
2. Treatment with the best standard of care practiced at each of the participating centers.
If recruited to the best standard of care group, patients will receive a chemotherapeutic
agent chosen based on their prior treatments and the standard of care practiced at each
treating center.
If recruited to the NovoTTF-100A group, the patients will be treated continuously until tumor
progression. NovoTTF-100A treatment will consist of wearing four electrically insulated
electrodes on the head. Electrode placement will require shaving of the scalp before
treatment. Patients will continue treatment at home where they can maintain their regular
daily routine.
During the trial, regardless of whether assigned to the NovoTTF-100A treatment group or the
best standard of care group, patients will need to return once every month the hospital
outpatient clinics where they will be examined by a physician. These routine visits will
continue for as long as the patient's disease is not progressing.
During the visits to the clinic patients will be examined physically and neurologically, as
well as fill in neuro-cognitive questionnaires. Adverse events data will be collected from
all patients.. After this follow up plan, patients will be contacted once per month by
telephone to answer basic questions about their health status.
SCIENTIFIC BACKGROUND:
TTFields are alternating electric fields of low intensity. This means that they change their
direction repetitively many times a second. Since they change direction very rapidly (200
thousand times a second), they do not cause muscles to twitch, nor do they have any effects
on other electrically activated tissues in the body (brain, nerves and heart). Since the
intensities of TTFields in the body are very low, they do not cause heating.
The breakthrough finding made by NovoCure was that finely tuned alternating fields of very
low intensity, now termed TTFields (Tumor Treating Fields), cause a significant slowing in
the growth of cancer cells. Due to the unique geometric shape of cancer cells when they are
multiplying, TTFields cause the building blocks of these cells to move and pile up in such a
way that the cells physically explode. In addition, cancer cells also contain miniature
building blocks which act as tiny motors in moving essential parts of the cells from place to
place. TTFields cause these tiny motors to fall apart since they have a special type of
electric charge.
As a result of these two effects, cancer tumor growth is slowed and can even reverse after
continuous exposure to TTFields.
Other cells in the body (normal healthy tissues) are affected much less than cancer cells
since they multiply at a much slower rate if at all. In addition TTFields can be directed to
a certain part of the body, leaving sensitive areas out of their reach.
In conclusion, TTField hold the promise of serving as a brand new cancer treatment with very
few side effects and promising affectivity in slowing or reversing this disease.
The Borealis-2 Clinical Trial: A Randomized Phase 2 Study Comparing Docetaxel Alone to Docetaxel in Combination With OGX-427 in Patients With Relapsed or Refractory Metastatic Urothelial Carcinoma After Receiving a Platinum-containing Regimen: Hoosier Cancer Research Network GU12-160
OUTLINE: This is a multi-center study.
Eligible patients will be stratified based on time from prior systemic chemotherapy (< 3 vs ≥
3 months) and Bellmunt prognostic factors criteria, which include Eastern Cooperative
Oncology Group (ECOG) performance status >0, hemoglobin <10g/dL, and presence of liver
metastases (0 versus 1-3 risk factors). Within the strata, participants will be randomly
assigned with equal probability to either the investigational arm (Arm A: docetaxel +
OGX-427) or the control arm (Arm B: docetaxel alone).
INVESTIGATIONAL ARM OGX-427 + DOCETAXEL (Arm A):
LOADING DOSE PERIOD:
Participants randomized onto the investigational arm (Arm A) will receive OGX-427 beginning
with a loading dose period prior to the initiation of docetaxel treatment. The first dose of
OGX-427 for the loading dose period must be administered within 5 working days of
registration and randomization.
During the loading dose period, participants will receive three separate administrations of
600 mg OGX-427 intravenously (IV) (days -9 to -1). There must be at least one "non-infusion"
day between each administration of OGX-427 (i.e., every other day) during the loading dose
period and between the third loading dose of OGX-427 and day 1 of cycle 1. There should be no
more than 7 days between the last loading dose and day 1 of cycle 1.
TREATMENT PERIOD:
During the treatment period, participants randomized to this arm will receive:
- OGX-427 600 mg IV weekly on days 1, 8, and 15 of each 21-day cycle. OGX-427 must be
administered prior to docetaxel on day 1 of each cycle.
- Docetaxel (75 mg/M2) IV on day 1 of each 21-day cycle. Docetaxel should be administered
immediately following the completion of the OGX-427 infusion.
OGX-427 MAINTENANCE:
Following completion of 10 cycles of docetaxel, 600 mg OGX-427 will continue to be
administered by IV weekly as maintenance therapy for participants who do not have disease
progression (i.e., stable disease or better). Participants without documented disease
progression who have discontinued from study treatment not due to toxicity related to OGX-427
can also continue to receive OGX-427 maintenance as long as they have completed disease
assessments following at least 2 cycles of chemotherapy. Maintenance with OGX-427 will
continue until disease progression or unacceptable toxicity.
CONTROL ARM - DOCETAXEL ALONE (Arm B):
TREATMENT PERIOD:
During the treatment period, participants randomized to this arm will receive:
- Docetaxel (75 mg/M2) IV on day 1 of each 21-day cycle. The first dose of docetaxel must be
administered within 5 working days of registration and randomization. Participants will
continue to receive docetaxel on day 1 of each 21-day cycle until disease progression,
unacceptable toxicity related to docetaxel, voluntary patient withdrawal, or a maximum of 10
docetaxel cycles.
FOLLOW-UP FOR BOTH ARMS:
Imaging studies will be performed every 6 weeks (i.e., after completion of cycles 2, 4, 6, 8
and 10) until disease progression and with any sign or symptom of new or worsening disease;
computed tomography scan (CT) of chest/abdomen/pelvis is preferred but magnetic resonance
imaging scan(MRI) is acceptable, especially for participants with increased risk of
contrast-related nephropathy or other contraindications. For Arm A, scans will be performed
every 2 cycles (6 weeks) +/1 week during the 21-day cycles of docetaxel administration and
every 6 weeks during maintenance OGX-427 administration until disease progression; for Arm B,
scans will be performed every 6 weeks during the 21-day cycles of docetaxel administration
until disease progression. All scans should be completed before the subsequent cycle is
scheduled to begin. Bone scans will be repeated, if positive at baseline, every 6 weeks
during the first 4 cycles of treatment (i.e., at the end of cycles 2 and 4) and then every 12
weeks thereafter until disease progression (i.e., at the end of cycle 8, at end of treatment,
and during maintenance with OGX-427 [Arm A only]).
All participants will have an End of Treatment (EOT) visit when they discontinue study
treatment. All participants will be followed until documented disease progression.
Once disease progression is documented, participants will enter a survival follow-up period.
All participants must be followed for survival as the primary endpoint. During the survival
follow-up period, data will be collected every three months regarding further cancer therapy,
secondary malignancy, and survival status.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Life Expectancy: Greater than 3 months
Hematopoietic:
- Absolute neutrophil count(ANC)≥ 1,500/mcL
- Hemoglobin ≥ 8 g/dL
- Platelets ≥ 100,000/mcL
Hepatic:
- Bilirubin ≤ 1.1 x upper limit of normal (ULN) (≤ 2.0 x ULN if secondary to Gilbert's
disease)
- Aspartate transaminase (AST), serum glutamic oxaloacetic transaminase (SGOT)/alanine
transaminase (ALT), serum glutamic pyruvic transaminase (SGPT) ≤ 1.5 X institutional ULN
Renal:
- Serum creatinine ≤ 1.5 x ULN
Cardiac:
- Symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
myocardial infarction within 3 months of randomization.
Best Endovascular Versus Best Surgical Therapy in Patients With Critical Limb Ischemia
Male and female subjects aged 18 years or older will be randomized to receive either open
surgical treatment or endovascular treatment. They will be followed for at least 2 years and
up to 4 years and 2 months after treatment to primarily assess survival and major adverse
limb events in the index or treated limb, and secondarily, to determine clinical and cost
effectiveness outcomes after treatment. These outcomes (survival-free of major limb events
and clinical, functional and cost effectiveness) will be compared within two cohorts of
subjects: those with an available single-segment great saphenous vein, and those with an
alternative conduit. The null hypotheses for both cohorts is that there will be no difference
in MALE-free survival between best endovascular therapy and best surgical therapy.
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