0C-14-4 A Phase I, multi-center, non-randomized, open label, parallel-group study evaluating the pharmacokinetics and safety of regorafenib (BAY 73-4506) in cancer subjects with severe renal impairment compared to a control group
Regorafenib is a targeted agent that has been shown to have anti-cancer activity and has been approved for use in previously treated patients with advanced colorectal cancer and gastrointestinal stromal tumors. Regorafenib is processed in the body or metabolized mostly through the liver, but the FDA recommends that a pharmacokinetic (PK) study be conducted in patients with damaged kidney function since damaged kidney function can alter the PK of the drug. PK studies look at what the body does to the drug in terms of how it is absorbed, distributed, metabolized, and excreted. The PK of regorafenib has been studied in patients with mild kidney damage, but not in patients with severe kidney damage or end-stage kidney disease. This open-label, Phase 1 study is being done with a primary objective to evaluate the impact of severe kidney damage on the PK of regorafenib in subjects with advanced solid tumors as compared to those with normal kidney function. There will be 2 groups of kidney function evaluated (Group 1 Control: normal/mild damage, Group 2: severe damage).
Once patients have signed consent and are deemed eligible, they will be assigned to one of two groups according to their kidney function status. Each group will have a minimum of 12 subjects. The study will be done in 2 stages. In the first stage, all subjects will receive one dose of regorafenib and have PK bloods collected for up to 4 days. They will enter into the second phase if they are willing and the study doctor thinks that they will benefit. They will continue to have study visits and receive study drug until they have side effect(s) or a condition which necessitates their removal from the study, they are lost to follow up, their disease progresses, they become pregnant, the protocol is not followed, they withdraw consent, their study doctor thinks that being on the study is no longer in their best interest, or the sponsor stops the study.
The PK and safety data will be summarized and analyzed by kidney function group. Summary statistics will be presented by treatment group. Medical history findings will be summarized for all subjects. The primary pharmacokinetic analysis will be based on classification of renal function using the C-G formula. The following statistics will be calculated for each of the PK sampling points and characteristics: arithmetic mean, standard deviation and coefficient of variation (CV), geometric mean, geometric standard deviation (re-transformed standard deviation of the logarithms) and CV, minimum, median, maximum value and the number of measurements. Individual and geometric mean concentration vs. time curves of all analytes will be plotted by treatment using both linear and semilogarithmic scale. To compare the two kidney function groups, AUC(0-24)md estimated with nominal dosing will be analyzed assuming log-normally distributed data.
A Randomized, Double-blind, Multicenter, Phase III Study of Everolimus (RAD001) Plus Best Supportive Care Versus Placebo Plus Best Supportive Care in the Treatment of Patients With Advanced NET of GI or Lung Origin
This was a prospective, multi-center, randomized, double-blind, parallel-group,
placebo-controlled, two-arm Phase III study comparing the efficacy and safety of everolimus
10 mg daily to placebo in patients with advanced NET of GI or lung origin without a history
of, or current symptoms of carcinoid syndrome.
After assessment of eligibility, participants qualifying for the study were randomized in a
2:1 ratio to receive either everolimus or matching placebo. Participants received daily oral
doses of 10 mg everolimus or matching placebo as study drug. In both arms, the study drug was
combined with best supportive care and treatment cycles were defined as 28 days. Participants
were treated until disease progression as per Response Evaluation Criteria In Solid Tumors
(RECIST) 1.0, intolerable toxicity, death, lost to follow-up or consent withdrawal.
Regardless of the reason for study drug discontinuation, participants had a safety follow-up
visit scheduled 30 days after the last dose of the study drug.
Per data monitoring committee recommendation, all participants on treatment with placebo were
allowed to crossover to open-label treatment with everolimus. This change was implemented
through protocol amendment 3 (issued on 06-May-2016) after which remaining participants
entered into open-label phase of the study.
A Window of Opportunity Study of Taxanes in Head and Neck Cancer
PRIMARY OBJECTIVE:
I. To describe the phenotypical and functional changes of different T cell subsets within the
tumor microenvironment after treatment with FID-007.
SECONDARY OBJECTIVES:
I. To describe the adverse events associated with neoadjuvant FID-007 prior to surgery for
head and neck cancer.
II. To evaluate preliminary evidence of efficacy by describing the rate of major and complete
pathologic response.
III. To describe the rates of locoregional recurrence and rate of distant metastasis at 2
years after surgery.
EXPLORATORY OBJECTIVE:
I. Explore association between pathologic response and phenotypical and functional changes in
T cell subsets.
OUTLINE:
Patients receive FID-007 intravenously (IV) over 30 minutes once a week for 3 weeks on days
1, 8, and 15 of a single 28 day cycle in the absence of disease progression or unacceptable
toxicity. Patients then undergo standard of care surgery. Patients undergo computed
tomography (CT) or magnetic resonance imaging (MRI) during screening and blood sample
collection throughout the study.
After completion of study treatment, patients are followed up every 3 months for 2 years.
4P-10-8: PREVAIL: A Multinational Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Oral MDV3100 in Chemotherapy-Nave Patients with Progressive Metastatic Prostate Cancer Who Have Failed Androgen Deprivation Therapy
This is a research study for individuals who have been diagnosed with cancer of the prostate that is getting worse despite receiving hormone treatment. This study will use MDV3100, an experimental drug, that has not been approved for sale to the public by the United States Food and Drug Administration (US FDA) or other government and health regulatory agencies. The purpose of this study is to determine if MDV3100 will help the study participants live longer, if MDV3100 can delay the progression of cancer by increasing the amount of time before the cancer progresses, and to determine the safety of the study drug.MDV3100 is an experimental drug known as an androgen-receptor antagonist (it blocks the activity of the male sex hormones). It directly affects a key mechanism in the body that leads to prostate cancer cell death. Prostate cancers are initially dependent on the male hormone testosterone for growth. Hormonal therapies that lower testosterone or block the ability of testosterone to act at the level of the prostate cancer are currently among the most effective treatments for prostate cancers that have spread to other body organs (metastasized). The effectiveness of hormonal treatments, however, is not permanent, and over time many prostate cancers progress in spite of these treatments. This study is a multicenter, phase 3 double-blind placebo-controlled study. This study is a blinded study, which means that neither the study participants nor the study doctor will know if they are taking MDV3100 or placebo. The experimental drug, MDV3100 is provided as a 40 mg soft gelatin capsule and is indicated at a dose of 160 mg/day administered once daily. The study drug may be taken with or without food.The study drug will be continued as long as the study participant is tolerating the study drug and continues androgen deprivation treatment until confirmed disease progression through imaging.The safety of the study drug will be determined by the frequency of serious adverse events, frequency and severity of adverse events, frequency of study drug discontinuation due to adverse events as well as the frequency of new clinically significant changes in physical examination findings, vital signs, laboratory values and ECGs.The efficacy analyses will be conducted using the intent-to-treat population defined as all randomized participants.The study will be conducted at 225 locations worldwide. About 1,680 people will participate in this study, 10 will be from USC.
A Randomized Phase III Trial of Intravesical BCG veRsus Intravesical Docetaxel and GEmcitabine Treatment in BCG Naïve High Grade Non-Muscle Invasive Bladder Cancer (BRIDGE)
The primary objective of this study is to determine the event free survival (EFS) of
BCG-naïve high grade non-muscle invasive bladder cancer patients treated with intravesical
BCG vs Gemcitabine + Docetaxel. Secondary objectives are as follows: to compare changes in
cancer-specific and bladder cancer-specific QOL from baseline to treatment between BCG-naïve
high grade NMIBC patients receiving BCG and GEMDOCE, to determine the cystectomy free
survival (CFS) of BCG-naïve high grade NMIBC patients treated with intravesical BCG vs
GEMDOCE, to determine the progression free survival (PFS) of BCG-naïve high grade NMIBC
patients treated with intravesical BCG vs GEMDOCE, and to determine the safety and toxicity
of BCG-naïve high grade NMIBC patients treated with intravesical BCG vs GEMDOCE
A Randomized Phase III Study of Immune Checkpoint Inhibition With Chemotherapy in Treatment-Naive Metastatic Anal Cancer Patients
PRIMARY OBJECTIVE:
I. To demonstrate that anti-PD-1 therapy in combination with carboplatin/weekly paclitaxel
results in improved progression-free survival (PFS) versus systemic chemotherapy alone.
SECONDARY OBJECTIVES:
I. To demonstrate that anti-PD-1 therapy in combination with carboplatin/weekly paclitaxel
results in improved overall survival (OS) versus systemic chemotherapy alone.
II. To demonstrate that anti-PD-1 therapy in combination with carboplatin/weekly paclitaxel
results in improved objective response using Response Evaluation Criteria in Solid Tumors
(RECIST) version (v)1.1 versus systemic chemotherapy alone.
III. To evaluate toxicity profiles of the two regimens.
OUTLINE: Patients are randomized to 1 of 2 arms. Randomization will be 2:1 favoring the
experimental regimen, Arm B.
ARM A: Patients receive paclitaxel intravenously (IV) on days 1, 8, and 15 of each cycle, and
carboplatin IV on day 1 of each cycle. Treatment repeats every 28 days for up to 6 cycles in
the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive nivolumab IV over 30 minutes on days 1 and 15 of cycle 1 and then on
day 1 only of subsequent cycles, paclitaxel IV on days 1, 8, and 15 of each cycle, and
carboplatin on day 1 of each cycle. Treatment repeats every 28 days for up to 6 cycles for
carboplatin and paclitaxel, and up to 2 years for nivolumab in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 1 month, then every 3 months
for 2 years.
Phase Ib/II Trial of Copanlisib in Combination With Trastuzumab and Pertuzumab After Induction Treatment of HER2 Positive (HER2+) Metastatic Breast Cancer (MBC) With PIK3CA Mutation or PTEN Mutation
PRIMARY OBJECTIVES:
I. To determine the safety and recommended phase 2 dose (RP2D) of the combination of
copanlisib, trastuzumab and pertuzumab in patients with metastatic epidermal growth factor
receptor 2 (HER2)-positive breast cancer. (Phase Ib) II. To assess the benefit of adding
copanlisib to trastuzumab and pertuzumab in HER2-positive metastatic breast cancer patients
with PIK3CA mutations or PTEN mutation receiving maintenance therapy after induction
treatment, as measured by progression free survival (PFS). (Phase II)
SECONDARY OBJECTIVES:
I. To assess the benefit of adding copanlisib to trastuzumab and pertuzumab in HER2-positive
metastatic breast cancer patients with PIK3CA mutations or PTEN mutation receiving
maintenance therapy after induction treatment, as measured by overall survival (OS). (Phase
II) II. To evaluate the safety of copanlisib given at the RP2D in combination with
trastuzumab and pertuzumab. (Phase II)
EXPLORATORY OBJECTIVES:
I. To correlate PFS and OS of the patients who receive the triplet combination with:
Ia. The number of induction cycles. Ib. Hormone receptor status (estrogen receptor [ER] and
progesterone receptor [PR]).
Ic. PTEN loss by immunohistochemistry (IHC). Id. PIK3CA mutations or PTEN mutations. (Phase
Ib)
II. To assess PTEN IHC, Ki-67 IHC and cleaved caspase-3 IHC and to perform molecular
profiling assays on malignant and normal tissues, including, but not limited to, whole exome
sequencing (WES) and messenger ribonucleic acid (RNA) sequencing (RNAseq), in order to:
IIa. Identify potential predictive and prognostic biomarkers associated with treatment
outcomes (PFS and OS) with the addition of copanlisib to dual HER2-targeted treatment.
IIb. Identify resistance mechanisms using genomic deoxyribonucleic acid (DNA)- and RNA-based
assessment platforms.
III. To contribute genetic analysis data from de-identified biospecimens to Genomic Data
Commons (GDC), a well annotated cancer molecular and clinical data repository, for current
and future research; specimens will be annotated with key clinical data, including
presentation, diagnosis, staging, summary treatment, and if possible, outcome.
IV. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA
analysis), and nucleic acids obtained from patients at the Experimental Therapeutics Clinical
Trials Network (ETCTN) Biorepository at Nationwide Children's Hospital.
OUTLINE:
PHASE I: Patients receive copanlisib intravenously (IV) over 60 minutes on days 1 and 8.
Patients also receive trastuzumab IV over 30-90 minutes and pertuzumab IV over 30-60 minutes
on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable
toxicity.
PHASE II: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive copanlisib IV over 60 minutes on days 1 and 8. Patients also receive
trastuzumab IV over 30-90 minutes and pertuzumab IV over 30-60 minutes on day 1. Cycles
repeat every 21 days in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive trastuzumab IV over 30-90 minutes and pertuzumab IV over 30-60
minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, patients are followed up within 30 days and at 3 months.
A Phase I Study of Anetumab Ravtansine in Combination With Either Anti-PD-1 Antibody, or Anti-CTLA4 and Anti-PD-1 Antibodies or Anti-PD-1 Antibody and Gemcitabine in Mesothelin-Positive Advanced Pancreatic Adenocarcinoma
PRIMARY OBJECTIVE:
I. To evaluate the safety and tolerability of anetumab ravtansine with the following
combinations in patients with mesothelin positive pancreatic adenocarcinoma.
SECONDARY OBJECTIVES:
I. To assess the preliminary anti-tumor activity of anetumab ravtansine (anetumab) in
combination with nivolumab, nivolumab and ipilimumab, nivolumab and gemcitabine hydrochloride
(gemcitabine) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
overall response rate (ORR).
II. To characterize the pharmacokinetics (PK) profile of anetumab (apparent diffusion
coefficient [ADC]), total antibody (ADC and cleaved free antibody), DM4 and DM4-Me (S-Methyl
metabolite of DM4).
III. To evaluate the tumor microenvironment and immune changes in tumor and peripheral blood
over the course of treatment to identify predictors of response or resistance to treatment.
IV. To measure the progressive disease (PD) effects of this combination including molecular
and immune biomarkers in tumor biopsies and peripheral blood.
EXPLORATORY OBJECTIVES:
I. To characterize mesothelin, PD-L1, CD3, CD4, CD8 expressions at baseline and after
treatment in mesothelin positive pancreatic cancer patients.
II. To evaluate level of soluble mesothelin and megakaryocyte potentiation factor (MPF) over
the course of treatment and to correlate these biomarkers with clinical outcome.
III. To perform whole exome sequencing (WES) +/- ribonucleic acid sequencing (RNAseq) in the
tumor biopsy specimens and correlation genomic (e.g. mutational burden) and transcriptomic
biomarkers with clinical outcome.
IV. To evaluate mononuclear phagocyte system (MPS) function, Fc-gamma receptors (FcgammaRs)
and hormone and chemokine mediators as methods to evaluate factors affecting the PK and PD of
these agents.
V. To evaluate anti-drug antibody (ADA) titres changes pre and post treatment and correlate
them with PK, toxicity and responses.
OUTLINE: This is a dose-escalation study of anetumab ravtansine. Patients are assigned to 1
of 3 arms.
ARM I: Patients receive anetumab ravtansine intravenously (IV) over 1 hour on day 1 and
nivolumab IV over 30 minutes on day 8 of cycle 1 and on day 1 of subsequent cycles. Treatment
repeats every 21 or 28 days (cycle 1) for up to 17 cycles in the absence of disease
progression or unacceptable toxicity. Patients also undergo a biopsy and collection of blood
on study.
ARM II: Patients receive anetumab ravtansine IV over 1 hour on day 1 and nivolumab IV over 30
minutes on day 8 of cycle 1 and on day 1 of subsequent cycles. Patients also receive
ipilimumab IV over 30 minutes on day 8 of cycle 1 and on day 1 of cycles 2-4. Treatment
repeats every 21 or 28 days (cycle 1) for up to 17 cycles in the absence of disease
progression or unacceptable toxicity. Patients also undergo a biopsy and collection of blood
on study.
ARM III: Patients receive anetumab ravtansine IV over 1 hour on day 1 and nivolumab IV over
30 minutes on day 8 of cycle 1 and on day 1 of subsequent cycles. Patients also receive
gemcitabine hydrochloride over 30-40 minutes on days 1 and 8. Treatment repeats every 21 or
28 days (cycle 1) for up to 17 cycles in the absence of disease progression or unacceptable
toxicity. Patients also undergo a biopsy and collection of blood on study.
After completion of study treatment, patients are followed up every 8 weeks for up to 100
days, then every 12 weeks thereafter.
A Phase 1-2, First-in-Human Study of CX-2029 in Adults With Metastatic or Locally Advanced Unresectable Solid Tumors or Diffuse Large B-cell Lymphomas (PROCLAIM-CX-2029)
This is an open-label, Phase 1-2, first-in-human study for CX-2029 in subjects with
metastatic or locally advanced unresectable solid tumors or Diffuse large B-cell lymphoma
(DLBCL) without approved life-prolonging treatment options for their malignancy.
The study is divided into 3 parts (arms), as follows:
- Part A: Dose escalation and determination of the Maximum tolerated dose (MTD) and/or
Recommended Phase 2 dose (RP2D)
- Part B: Characterization of CX-2029 in the Tumor microenvironment (TME) in subjects with
select tumor types using previously cleared dose levels from Part A
- Part C: Expansions in select tumor types at the MTD/RP2D as established in Part A
PRESENT: Prevention of Recurrence in Early-Stage, Node-Positive Breast Cancer With Low to Intermediate HER2 Expressions With NeuVax™Treatment
This is a multicenter, multinational, prospective, randomized, double-blind, controlled Phase
3 study.
The subjects eligible for this trial have an early stage node-positive breast cancer. Their
tumors express low or intermediate levels of the HER2 protein. NeuVax™ will be administered
after completion of front-line, standard of care therapy (surgery, radiation therapy, and
chemotherapy) and can be given concomitantly with physician prescribed endocrine treatment.
NeuVax™ is the immmunodominant nonapeptide derived from the extracellular domain of the HER2
protein, a well-established target for therapeutic intervention in breast carcinoma. The
nelipepimut sequence stimulates specific CD8+ cytotoxic T lymphocytes (CTL) following binding
to HLA-A2/A3 molecules on antigen presenting cells (APC). These activated specific CTLs
recognize, neutralize and destroy through cell lysis HER2 expressing cancer cells, including
occult cancer cells and micrometastatic foci. The nelipepimut immune response can also
generate CTLs to other immunogenic peptides through inter- and intra-antigenic epitope
spreading. Based on a successful Phase 2 trial, which achieved its primary endpoint of DFS,
the Food and Drug Administration (FDA) granted NeuVax a Special Protocol Assessment (SPA) for
its Phase 3 PRESENT (Prevention of Recurrence in Early-Stage, Node-Positive Breast Cancer
with Low to Intermediate HER2 Expression with NeuVax Treatment) study.
The active portion of the study will last three years (36 months). The follow-up will last
from 5 to 10 years.
Endpoints:
1. Primary efficacy endpoint:
- 3-year DFS
2. Secondary efficacy endpoints:
- 5- and 10-year DFS
- 3-year OS
- 5- and 10-year OS
- Safety profile, and adverse events (AEs)
- Patterns of recurrence to include Time to recurrence (TTR), time to local
recurrence (TTLR), time to distant recurrence (TTDR), time to bone metastases
(TTBM)
Safety Assessments:
Subjects will be assessed at every study visit for the safety endpoints, AEs,vital signs,
physical examinations and laboratory data; yearly follow-up of survival will include imaging
studies, ECGs, MUGA or ECHO scans and concomitant medications.
A Phase 1 Study of IPdR in Combination With Capecitabine and Radiotherapy in Rectal Cancer
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) of oral (PO) ropidoxuridine (IPdR) when
administered with capecitabine (825 mg/m^2 twice daily [BID]) and radiation therapy (RT)
(50.4 Gy in 28 fractions).
II. To determine the toxicities Common Terminology Criteria for Adverse Events (CTCAE)
version (v) 5 of the combined modality therapy, IPdR + capecitabine + RT.
SECONDARY OBJECTIVES:
I. To establish the pharmacokinetics (PK) of once daily (QD) IPdR when combined with
capecitabine.
II. To evaluate iododeoxyuridine (IUdR) incorporation in circulating granulocytes and
correlate these levels with IPdR plasma PK and clinical/laboratory toxicities.
III. To assess IUdR incorporation in tumor cells obtained from the surgical resection
specimen and correlate IUdR incorporation in tumor cells with IPdR PK.
IV. To assess IUdR incorporation in tumor cells obtained from the surgical resection specimen
and correlate IUdR incorporation in tumor cells with tumor response as measured by
pathological complete response (pCR) rate and neoadjuvant rectal (NAR) score.
V. To determine the pCR rate of IPdR + capecitabine + RT at the IPdR MTD as a measure of
anti-tumor activity.
VI. To determine the NAR score of IPdR + capecitabine + RT at the IPdR MTD.
EXPLORATORY OBJECTIVES:
I. To explore the relationship between extent of exposure to RT and the development and
severity of adverse events.
II. To explore the drug/drug/metabolite interactions between capecitabine, IPdR, and their
metabolites.
OUTLINE: This is a phase IA, dose-escalation study of ropidoxuridine followed by a phase IB
study.
Patients receive ropidoxuridine PO QD over 7 days per week and capecitabine PO BID over 6
days per week for 6 weeks. Patients also undergo radiation therapy over 1 fraction per day
for 5 days per week (Monday-Friday) during weeks 1-5 and for 3 days during week 6 in the
absence of disease progression or unacceptable toxicity. Approximately 8-12 weeks after
completion of treatment with ropidoxuridine, capecitabine, and radiation therapy, patients
undergo standard of care surgery.
After completion of study treatment, patients are followed up at 4 and 8-12 weeks following
chemoradiation therapy.
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