A Randomized Phase II Trial of Adjuvant Nivolumab With or Without Cabozantinib in Patients With Resected Mucosal Melanoma
PRIMARY OBJECTIVE:
I. To compare the efficacy of adjuvant nivolumab (480 mg every [q]4 weeks) versus nivolumab
plus cabozantinib s-malate (cabozantinib) (40 mg daily) in patients with mucosal melanoma.
SECONDARY OBJECTIVES:
I. To compare overall survival between the two adjuvant therapies. II. To evaluate the
adverse effects in each arm. III. To assess the correlation between PD-L1 expression in tumor
cells with survival (recurrence free survival [RFS] and overall survival [OS]).
IV. To evaluate the overall response rate (ORR), duration of response (DOR), progression free
survival (PFS), and OS of nivolumab plus cabozantinib in patients who cannot undergo gross
total resection of disease or have metastatic disease at baseline.
V. Results of the primary analysis will be examined for consistency, while taking into
account the stratification factors and/or covariates of baseline quality of life (QOL) and
fatigue.
OUTLINE: Patients whose tumor has been fully removed by surgery are randomized to Arm 1 or
Arm 2. Patients whose tumor has not been fully removed by surgery or has spread are assigned
to Arm 3.
ARM 1: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1 and
cabozantinib orally (PO) once daily (QD) of each cycle. Treatment repeats every 28 days for
up to 13 cycles in the absence of disease progression or unacceptable toxicity.
ARM 2: Patients receive nivolumab IV over 30 minutes on day 1 and placebo PO QD of each
cycle. Treatment repeats every 28 days for up to 13 cycles in the absence of disease
progression or unacceptable toxicity.
ARM 3: Patients receive nivolumab IV over 30 minutes and cabozantinib PO QD of each cycle.
Treatment repeats every 28 days for up to 26 cycle in the absence of disease progression or
unacceptable toxicity.
Patients undergo echocardiogram (ECHO) during screening and as clinically indicated
throughout the trial. Patients may undergo computed tomography (CT), magnetic resonance
imaging (MRI), or positron emission tomography (PET)/CT at baseline, CT and MRI may be
repeated every 6 months on study. Additionally, patients may undergo stool sample collection
at baseline, and blood and tissue sample collection at baseline and on the trial.
After completion of study treatment, patients are followed up every 3 months until disease
progression, and then every 6 months for up to 5 years from registration or until death.
A Phase II, Single Arm, Open Label Study of Treatment-free Remission in Chronic Myeloid Leukemia (CML) Chronic Phase (CP) Patients After Achieving Sustained MR4.5 on Nilotinib
The Primary objective was to evaluate the proportion of patients in TFR within 48 weeks
following nilotinib cessation.
This study originally consisted of seven phases (five treatment phases and two treatment-free
phases) from which two were the focus of this primary analysis report (consolidation, TFR and
treatment re-initiation) The study consisted of 2 main phases: Consolidation and TFR
Nilotinib treatment consolidation phase (NTCS): Patients who satisfied all
inclusion/exclusion criteria were enrolled in the consolidation phase and continued to
receive nilotinib for 52 weeks at the dose which the patient was receiving prior to study
entry. If a patient maintained MR4.5 throughout the consolidation phase, he/she was eligible
to enter in the TFR phase. If a patient had confirmed loss of MR4.5 during the consolidation
phase, he/she was not eligible to enter in the TFR phase and continued nilotinib treatment.
Nilotinib TFR phase: Patients who were eligible to enter in the TFR phase after completing
the 52 week consolidation phase stopped taking nilotinib on the first day of the TFR phase.
Duration of this phase was up to 520 weeks after the last patient enters in the TFR phase.
Nilotinib treatment re-initiation phase (NTRI): If a patient had a confirmed loss of MR4 (two
consecutive BCR-ABL >0.01% IS) or loss of MMR (BCR-ABL >0.1% IS) in the TFR phase, the
patient restarted nilotinib treatment. Patients will be on nilotinib treatment for up to 520
weeks after the last patient entered the nilotinib TFR phase, or until a patient experience
unacceptable toxicity, disease progression and/or treatment discontinued at the discretion of
the Investigator or if the patient withdrew consent. Nilotinib cessation was not attempted
for a second time in the patient who reinitiated treatment or discontinued following the TFR
phase.
Nilotinib treatment continuation phase (NTCT) and Nilotinib treatment prolonged continuation
phase (NTCT-P): Patients who were not eligible to enter into the TFR phase after completing
the 52-week NTCS phase entered the nilotinib treatment continuation (NTCT) phase and would
continue treatment with nilotinib for another 52 weeks (a total of 104 weeks of treatment).
Patients who were not able to maintain MR4.5 and had a confirmed loss of MR4.5 during the
NTCT phase were not eligible to enter the TFR-2 phase. These patients entered into the
nilotinib prolonged treatment continuation phase (NTCT-P) and continued nilotinib treatment
until 520 weeks after the last patient entered the nilotinib TFR phase, or until the patients
experience unacceptable toxicity, disease progression and/or treatment would be discontinued
at the discretion of the Investigator or withdrawal of consent.
Nilotinib TFR-2 phase: Patients who maintained MR4.5 during the NTCT phase were eligible to
cease nilotinib treatment and enter the TFR-2 phase. The duration of the nilotinib TFR-2
phase is up to 520 weeks after the last patient entered the TFR phase. Patients stopped
taking nilotinib therapy on the day they entered the TFR-2 phase.
Nilotinib treatment re-initiation-2 (NTRI-2): If a patient had a loss of MMR or a confirmed
loss of MR4 during the TFR-2 phase, he/she entered the nilotinib treatment re-initiation-2
(NTRI-2) phase and resumed nilotinib treatment at a dose of either 300 mg or 400 mg bid.
Safety follow-up was performed within 30 days after the last dose of study treatment or the
last day in TFR/TFR-2.
Post-treatment follow-up visits were performed every 12 weeks up to 520 weeks after the last
patient entered the nilotinib TFR phase.
A Phase III, Randomized, Open Label, Multicenter, Controlled Trial of Niraparib Versus Physician's Choice in Previously-treated, HER2 Negative, Germline BRCA Mutation-positive Breast Cancer Patients
This is a phase III, randomized, open label, multicenter, controlled trial of niraparib
versus physician's choice in previously-treated, HER2 negative, germline BRCA
mutation-positive breast cancer patients. Niraparib is an orally active PARP inhibitor.
Niraparib (in a 2:1 ratio) will be administered once daily continuously during a 21-day
cycle. Physician's choice will be administered on a 21-day cycle. Health-related quality of
life will be measured. The safety and tolerability will be assessed by clinical review of
adverse events (AEs), physical examinations, electrocardiograms (ECGs), and safety laboratory
values.
Pivotal, Open-label, Randomized Study of Radiosurgery With or Without Tumor Treating Fields (TTFields) for 1-10 Brain Metastases From Non-small Cell Lung Cancer (NSCLC).
PAST PRE-CLINICAL AND CLINICAL EXPERIENCE:
The effect of the electric fields (TTFields, TTF) has demonstrated significant activity in in
vitro and in vivo NSCLC pre-clinical models both as a single modality treatment and in
combination with chemotherapies. TTFields have also shown to inhibit metastatic spread of
malignant melanoma in in vivo experiment.
In a pilot study, 42 patients with advanced NSCLC who had tumor progression after at least
one line of prior chemotherapy, received pemetrexed together with TTFields (150 kHz) applied
to the chest and upper abdomen until disease progression (Pless M., et al., Lung Cancer
2011). Efficacy endpoints were remarkably high compared to historical data for pemetrexed
alone.
In addition, a phase III trial of Optune® (200 kHz) as monotherapy compared to active
chemotherapy in recurrent glioblastoma patients showed TTFields to be equivalent to active
chemotherapy in extending survival, associated with minimal toxicity, good quality of life,
and activity within the brain (14% response rate) (Stupp R., et al., EJC 2012). Finally, a
phase III trial of Optune® combined with maintenance temozolomide compared to maintenance
temozolomide alone has shown that combined therapy led to a significant improvement in both
progression free survival and overall survival in patients with newly diagnosed glioblastoma
without the addition of high grade toxicity and without decline in quality of life (Stupp R.,
et al., JAMA 2015).
Applying TTFields at 150 kHz to the brain for the treatment of 1-5 brain metastasis from
NSCLC using the NovoTTF-100M device has been demonstrated to be safe in a pilot study, where
patients were randomized after local therapy of their brain metastasis by neurosurgery and/or
stereotactic radiosurgery to receive either NovoTTF-100M treatment or supportive care alone.
Eighteen (18) patients have been enrolled in the study. There have been no device-related
serious adverse events (SAE) reported to date (Brozova H., et al., Neuro Oncol 2016).
DESCRIPTION OF THE TRIAL:
All patients included in this trial are patients with 1-10 brain metastases from NSCLC which
are amenable to stereotactic radiosurgery (SRS). In addition, all patients must meet all
eligibility criteria.
Eligible patients will be randomly assigned to one of two groups:
1. Patients undergo SRS followed by TTFields using the NovoTTF-200M System
2. Patients undergo SRS alone and receive supportive care. Patients in both arms of the
study may receive systemic therapy for their NSCLC at the discretion of their treating
physician.
Patients will be randomized at a 1:1 ratio. Baseline tests will be performed in patients
enrolled in both arms. If assigned to the NovoTTF-200M group, the patients will be treated
continuously with the device until second intracranial progression.
On both arms, patients who recur anywhere in the brain will be offered one of the following
salvage treatments (according to local practice) including, but not limited to:
- Surgery
- Repeat SRS
- Whole brain radiotherapy (WBRT) Patients on the control arm will be offered to cross
over to the NovoTTF-200M arm of the study and receive TTFields with or without salvage
therapy for second intracranial progression if the investigator believes it is in the
best interest of the patient and patient agrees.
SCIENTIFIC BACKGROUND:
Electric fields exert forces on electric charges similar to the way a magnet exerts forces on
metallic particles within a magnetic field. These forces cause movement and rotation of
electrically charged biological building blocks, much like the alignment of metallic
particles seen along the lines of force radiating outwards from a magnet.
Electric fields can also cause muscles to twitch and if strong enough may heat tissues.
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 (150
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 electrically- charged cellular components of these cells to
change their location within the dividing cell, disrupting their normal function and
ultimately leading to cell death.. 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 interfere with the normal orientation of these tiny motors related to other cellular
components since they are electrically-charged as well. As a result of these two effects,
tumor cell division is slowed, results in cellular death or reverses 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. Finally, the
frequency of TTFields applied to each type of cancer is specific and may not damage normally
dividing cells in healthy tissues. In conclusion, TTFields hold the promise of serving as a
brand new treatment for brain metastases from NSCLC with very few side effects.
A Single-arm, Multicenter Study to Assess the Efficacy, Safety, and Tolerability of Ropeginterferon Alfa-2b-njft (P1101) in Adult Patients With Essential Thrombocythemia
PharmaEssentia is developing a pegylated (PEG) IFN-α product, P1101, for the treatment of
Essential Thrombocythemia (ET) as lack of disease modifying therapies in essential ET
constitutes a serious issue in modern hematology.
Ropeginterferon alfa-2b-njft (P1101) may represent an effective, well-tolerated treatment
with the ability to provide a deeper response and superior control of important blood
parameters with the potential to alter the course of the disease and prevent progression to
post-ET myelofibrosis (MF) and/or secondary acute myeloid leukemia (sAML). Ropeginterferon
alfa-2b-njft (P1101) is currently being evaluated in comparison to ANA in the ongoing global
Phase 3 clinical study, SURPASS ET.
Enrolled patients will receive P1101 over 13 months followed by an extension period.
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.
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Trial of the Effects of GC4419 on Severe Oral Mucositis in Patients Receiving Cisplatin + Intensity-modulated Radiation Therapy (IMRT) for Locally Advanced Non-Metastatic Squamous Cell Carcinoma (SCC) of the Oral Cavity/Oropharynx
GT-201 is a randomized, double-blind, placebo-controlled, multi-center study conducted in the
U.S. to evaluate GC4419 administered via an intravenous line (IV) for the reduction of
incidence, duration, and severity of radiation induced oral mucositis in patients receiving
cisplatin plus intensity-modulated radiation therapy for post-operative, or definitive
treatment of locally advanced, non-metastatic squamous cell carcinoma of the head and neck,
limited to the oral cavity or oropharynx. Patients will be randomized equally to 1 of 3
treatment arms:
Arm A: 30 mg GC4419 per day (60 min IV infusion to complete within 60 minutes prior to IMRT),
concurrent with daily fractions of IMRT (2.0 - 2.2 Gy) to a total of 60 - 72 Gy over
approximately 7 weeks, plus cisplatin administered 80 - 100 mg/m2 once every three weeks for
3 doses or 30 - 40 mg/m2 once weekly for 6-7 doses (investigator's choice).
Arm B: 90 mg GC4419 per day (60 min IV infusion to complete within 60 minutes prior to IMRT),
concurrent with daily fractions of IMRT (2.0 - 2.2 Gy) to a total of 60 - 72 Gy over
approximately 7 weeks, plus cisplatin administered 80 - 100 mg/m2 once every three weeks for
3 doses or 30 - 40 mg/m2 once weekly for 6-7 doses (investigator's choice).
Arm C: Placebo daily (60 min IV infusion to complete within 60 minutes prior to IMRT),
concurrent with daily fractions of IMRT (2.0 - 2.2 Gy) to a total of 60 - 72 Gy over
approximately 7 weeks, plus cisplatin administered 80 - 100 mg/m2 once every three weeks for
3 doses or 30 - 40 mg/m2 once weekly for 6-7 doses (investigator's choice).
Planned radiation fields in all 3 arms must include at least two oral sites (buccal mucosa,
floor of mouth, tongue, soft palate) with each site receiving a dose of at least 50 Gy.
All patients will be assessed twice weekly for oral mucositis per WHO grading criteria until
the completion of IMRT, and once weekly thereafter (if necessary) for 8 weeks, or until oral
mucositis resolves to ≤ Grade 1.
Approximately 200 total to ensure that roughly 60 patients per arm receive study drug and
complete requirements for primary endpoint analysis, which is defined as patients receiving a
minimum cumulative dose of 60 Gy.
A Randomized, Double-blind Phase 2 Study Comparing Gemcitabine and Cisplatin in Combination With OGX-427 or Placebo in Patients With Advanced Transitional Cell Carcinoma
Following 3 loading doses, participants receive chemotherapy and study drug on a 21-day cycle
during the Treatment Period (Chemotherapy Period) until disease progression, completion of 6
cycles, toxicity or voluntary participant withdrawal. Participants who do not have documented
disease progression and have completed a minimum of four cycles of chemotherapy continue to
receive weekly Study Drug maintenance therapy during the Maintenance Period until disease
progression or the participant fulfills one of the other reasons for withdrawal from protocol
treatment, unless they have been discontinued from protocol treatment for unacceptable
toxicity related to study drug. All participants have an End of Treatment (EOT) visit when
they are withdrawn from all study treatment (chemotherapy and maintenance). All participants
are followed until documented disease progression. Once disease progression is documented,
participants enter a Survival Follow-up Period during which data are collected regarding
further cancer therapy, secondary malignancy, and survival status.
A Phase 1/2 Open-label, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of PC14586 in Patients With Locally Advanced or Metastatic Solid Tumors Harboring a TP53 Y220C Mutation (PYNNACLE)
PC14586 (INN: rezatapopt) is a first-in-class, oral, small molecule p53 reactivator that is
selective for the TP53 Y220C mutation.
The primary objective of Phase 1 Monotherapy is to establish the maximum tolerated dose (MTD)
and recommended Phase 2 dose (RP2D) of PC14586 (INN: rezatapopt). Secondary objectives are to
characterize the pharmacokinetic (PK) properties, safety and tolerability, and to assess
preliminary efficacy including overall response rate (ORR).
The primary objective of Phase 1b Combination Therapy is to establish the MTD/RP2D of PC14586
(INN: rezatapopt) when administered in combination with pembrolizumab. Secondary objectives
of Phase 1b Combination Therapy are to characterize PK, safety and tolerability, and to
assess preliminary efficacy of PC14586 (INN: rezatapopt) when administered in combination
with pembrolizumab, including ORR.
The primary objective of Phase 2 Monotherapy is to evaluate the efficacy of PC14586 (INN:
rezatapopt) at the RP2D including the ORR in the Ovarian Cancer Cohort and the ORR across all
cohorts as determined by blinded independent central review. Secondary objectives of Phase 2
are to characterize the safety, PK properties, quality of life, and other efficacy measures
of PC14586 (INN: rezatapopt) at the RP2D.
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