This study has been transitioned to CTIS with ID 2024-510605-28-00 check the CTIS register for the current data. Primary Objective• To compare the progression free survival (PFS) of programmed death-ligand 1 (PD-L1) positive patients with Stage III…
ID
Source
Brief title
Condition
- Ovarian and fallopian tube disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy Analysis
Primary Efficacy Endpoint
This study has dual primary efficacy endpoints: PFS in PD-L1 positive patients
and PFS in all patients. The primary efficacy endpoint PFS is defined as the
time from the date of treatment randomization to the date of first
documentation of progression or death by any cause in the absence of
progression, whichever occurs first, as determined by the Investigator.
Progression will be assessed by RECIST v.1.1 criteria based on Investigator*s
assessment.
Exploratory Efficacy Endpoint
The following exploratory efficacy endpoint will be evaluated:
• DpOR defined as the maximal amount of tumor shrinkage observed. DpOR will be
assessed per RECIST v1.1 and irRECIST criteria in patients with measurable
disease.
• PFS in Arm 1 and Arm 2 BRCAwt patients who receive bevacizumab will be
assessed per RECIST v1.1.
• PFS per Investigator-assessed RECIST v.1.1 criteria in patients with HRR/HRD
status
Interim Analysis
Planned periodic safety analyses will be conducted by the Independent Data
Monitoring Committee (IDMC) after 24 randomized patients have completed at
least 2 cycles of treatment. Details of safety analyses are placed in the IDMC
charter.
A second safety analysis will occur when approximately 60 patients in Arm 3
have completed at least 2 cycles of the maintenance treatment. After that,
periodic safety review will be conducted every 6 months as determined by the
IDMC.
Biomarker Analysis
Biomarkers related to ovarian cancer, PARP inhibition, and PD 1 therapy may be
evaluated (eg, DNA repair deficiency, PD-L1 expression, and immune biomarkers).
Immunogenicity Analysis
Blood samples for the determination of dostarlimab ADAs will be part of the
same blood collections as those taken for the PK assessments. ADAs will be
analyzed in a tiered approach using electro chemiluminescence (ie, Screening,
confirmation, titer, and neutralizing antibody assay), if appropriate.
PK Analysis
Blood samples for PK will be collected at the time points specified in the
sampling schedule.
Parameters of interest are minimum observed concentration (Cmin) and maximum
observed concentration (Cmax) for niraparib and dostarlimab.
Secondary outcome
Secondary Efficacy Endpoints
For both PD-L1 positive and all patients, the following secondary efficacy
endpoints will be evaluated:
• BICR determined PFS per RECIST v1.1
• PFS, per irRECIST criteria based on Investigator*s assessment
• OS, as measured from the date of randomization to the date of death by any
cause
• The observed change from baseline and time to symptom worsening in the EQ 5D
5L, EORTC QLQ C30, and EORTC QLQ OV28 HRQoL assessments
• TFST, defined as the date of randomization in the current study to the start
date of the first subsequent anticancer therapy or death
• TSST, defined as the date of randomization in the current study to the start
date of the second subsequent anticancer therapy or death
• PFS2, defined as the time from randomization to the earlier date of
assessment of progression on the next anticancer therapy following study
treatment or death by any cause as assessed by the Investigator
• ORR, defined as the percentage of patients with complete response (CR) or
partial response (PR) on study treatment as assessed by RECIST v.1.1 criteria
for patients with measurable disease. ORR will also be assessed per irRECIST
criteria.
• pCR rate, per Investigator assessment, defined as the rate of pathologic
complete response as assessed by the evaluation of residual microscopic disease
at the time of surgery in neoadjuvant patients
• DOR, defined as the time from first documentation of CR or PR until the time
of first documentation of PD as assessed by RECIST v.1.1, or death by any cause
in the absence of progression, whichever occurs first. DOR will also be
assessed per irRECIST criteria.
• DCR, defined as the proportion of patients with a best overall response of
CR, PR, or stable disease, as assessed by RECIST v.1.1 criteria. DCR will also
be assessed per irRECIST criteria.
• MPFS, defined as the time from the date of the first maintenance period dose
to the date of first documentation of progression or death by any cause in the
absence of progression, whichever occurs first, as determined by the
Investigator. Progression will be assessed by RECIST v.1.1 criteria. MPFS will
also be assessed per irRECIST criteria.
Safety Analysis (Secondary Endpoint)
The core safety analyses will be based on the Arm 2 and Arm 3 safety
populations. In addition, a safety analysis will also be performed on the Arm 1
safety population for supportive analysis.
Safety will be evaluated based on the incidence of TEAEs, SAEs, treatment
discontinuations or dose delays or dose reductions due to AEs, irAEIs, changes
in ECOG performance status, changes in clinical laboratory results (hematology
and chemistry), vital sign measurements, observations during physical
examination, and use of concomitant medications. All AEs will be coded using
the current version of the Medical Dictionary for Regulatory Activities coding
system.
Background summary
Please see the protocol, section 1. Introduction.
Study objective
This study has been transitioned to CTIS with ID 2024-510605-28-00 check the CTIS register for the current data.
Primary Objective
• To compare the progression free survival (PFS) of programmed death-ligand 1
(PD-L1) positive patients with Stage III or IV high-grade nonmucinous
epithelial ovarian cancer treated with platinum-based combination therapy,
dostarlimab, and niraparib to standard-of-care (SOC) platinum-based combination
therapy.
• To compare the PFS of all patients with Stage III or IV high-grade
nonmucinous epithelial ovarian cancer treated with platinum-based combination
therapy, dostarlimab, and niraparib to SOC platinum-based combination therapy
The primary PFS analysis will be based upon the Investigator*s assessment per
Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 criteria.
Secondary Objectives
For PD-L1 positive patients and all patients, secondary objectives will
evaluate:
• Overall survival (OS)
• Blinded Independent Central Review (BICR)-determined PFS per RECIST v1.1
• Safety and tolerability of all treatments
• Health related quality of life (HRQoL)
• Time to first subsequent therapy (TFST)
• Time to second subsequent therapy (TSST)
• Time from treatment randomization to the earliest date of assessment of
progression on the next anticancer therapy following study treatment or death
by any cause (PFS2)
• Objective response rate (ORR) per RECIST v.1.1 for patients with measurable
disease at baseline scan
• Disease control rate (DCR) per RECIST v.1.1
• Maintenance progression free survival (MPFS) per RECIST v.1.1
• pharmacokinetics (PK) and immunogenicity of dostarlimab
• PK of niraparib
Exploratory Objectives
• To measure biomarkers related to ovarian cancer, poly (adenosine diphosphate
[ADP] ribose) polymerase (PARP) inhibition, and anti programmed death 1 (anti
PD 1) therapy, including deoxyribonucleic acid (DNA) repair pathways and immune
checkpoint pathways
• To compare the PFS, per Investigator-assessed RECIST v.1.1 criteria, of all
Arm 1 versus Arm 2 patients with wild-type breast cancer susceptibility gene
(BRCAwt) who receive bevacizumab
• To evaluate PFS per Investigator-assessed RECIST v.1.1 criteria in patients
with homologous recombinant repair (HRR)/ homologous recombinant deficiency
(HRD) status
Study design
This is a global, multicenter, randomized, double-blind, controlled Phase 3
study in patients with newly diagnosed, Stage III or IV high-grade nonmucinous
epithelial ovarian, fallopian tube, or peritoneal cancer (collectively referred
to as *ovarian cancer*). The currently recommended SOC chemotherapy therapy for
the first line treatment of Stage III or IV ovarian cancer is a combination of
paclitaxel carboplatin, with or without concurrent and maintenance bevacizumab.
Throughout this document *SOC* should be understood to mean
paclitaxel-carboplatin ± bevacizumab. The use of bevacizumab must be determined
prior to randomization.
The study is open to patients with inoperable ovarian cancer, patients who have
macroscopic residual disease at the end of the primary debulking surgery (PDS)
and have recovered from PDS and patients for whom platinum based combination
neoadjuvant chemotherapy (NACT) is planned. Patients with Stage IIIC disease
that has been completely resected (also known as complete cytoreduction score
of 0 [CC0] are eligible if the following criteria is present: aggregate >5 cm
extra-pelvic disease during PDS as assessed by the Investigator. The use of
bevacizumab is optional and permitted if considered SOC per local treatment
guidelines and/or practices.
All eligible enrolled patients will receive SOC during the Cycle 1 Chemotherapy
Run-In Period before randomization to study treatment at Cycle 2.
Treatment Arm 1 consists of SOC and intravenous (IV) dostarlimab-placebo
followed by oral niraparib-placebo and IV dostarlimab-placebo in the
maintenance phase of treatment. Arm 2 consists of SOC and IV
dostarlimab-placebo followed by oral niraparib and IV dostarlimab-placebo
maintenance therapy. Arm 3 consists of SOC and IV dostarlimab followed by oral
niraparib and IV dostarlimab maintenance therapy.
Randomization will be stratified by concurrent bevacizumab use, homologous
recombinant repair (HRR) mutation status (ie, BRCA-mutated [BRCAmut], BRCA
wild type HRR positive [BRCAwt HRRpos], and BRCA wild type HRR negative or not
determined [BRCAwt HRRneg/not determined]), and disease burden as defined by
Stage III cancer with residual disease <1 cm (ie, yes or no). To minimize bias,
patients, Investigators, and the site investigative staff will be blinded to
HRR status and treatment assignment.
This study is designed to enable rapid adaptation to evolving treatment
paradigms and provide Investigators with the current SOC for patients with
advanced ovarian cancer This ensures that study participants will have access
to contemporaneous SOC with or without investigational treatment while
maintaining the integrity of the study. Full details on adaptations to the
study design are located in the protocol.
In Amendment 3, dated 17 July 2019, subsequent to data made available from the
SOLO-1 study (a randomized Phase 3 study of olaparib maintenance treatment
versus placebo following first-line SOC therapy in patients with BRCA-mutated
Stage III/IV ovarian cancer), where it was reported that PARP inhibitor
maintenance provided significant clinical benefit in this population, newly
enrolled patients with BRCAmut in this study were randomized to Arm 2 or Arm 3
only. There was no change to patients with BRCAwt status; they continued to
be randomized to Arm 1, Arm 2, or Arm 3. Arm 1 BRCAmut patients who were in
the Chemotherapy Treatment Period when the amendment was implemented completed
the 6 cycles of chemotherapy. Following completion of the Chemotherapy
Treatment Period and confirmation of adequate hematologic parameters, these
patients were allowed to start niraparib maintenance therapy as *post-study
anticancer treatment* at the Investigator*s discretion. Arm 1 BRCAmut patients
who were in the Maintenance Treatment Period when the amendment was implemented
were allowed to start niraparib maintenance therapy as "post-study anticancer
treatment" if the time after Cycle 6 Day 1 of the Chemotherapy Treatment Period
was <=12 weeks. In order to facilitate this adaptation, Investigators were
unblinded for Arm 1 BRCAmut patients enrolled prior to implementation of this
amendment.
Recently, results from PRIMA, a randomized Phase 3 study of niraparib
maintenance therapy or placebo following first-line platinum therapy for Stage
III/IV ovarian cancer, and PAOLA-1, a randomized Phase 3 study of olaparib
maintenance therapy or placebo added to bevacizumab maintenance treatment
following first-line platinum therapy for Stage III/IV ovarian cancer became
available. The hazard ratio (HR) of 0.62 and 0.59, respectively, demonstrated
that a PARP inhibitor with or without bevacizumab prolonged PFS in all patients
with advanced ovarian cancer after response to first-line platinum-based
chemotherapy. Therefore, the currently recommended SOC therapy for the
maintenance treatment of Stage III or IV ovarian cancer is a combination of
paclitaxel carboplatin with or without bevacizumab, and a PARP inhibitor.
As a result, following Sponsor and Steering Committee discussions, patients
will not be enrolled into Arm 1 after Amendment 4 is approved at each site.
Patients in Arm 1, Chemotherapy Treatment Period who are receiving bevacizumab
when Amendment 4 is implemented, may continue the 6 cycles of chemotherapy.
Following completion of the Chemotherapy Treatment Period and confirmation of
adequate hematologic parameters, those patients may start bevacizumab
maintenance therapy at the Investigator*s discretion. Patients in Arm 1,
Maintenance Treatment Period who are receiving bevacizumab when Amendment 4 is
implemented may continue bevacizumab maintenance therapy at the Investigator*s
discretion. Investigators will remain blinded for those patients enrolled in
Arm 1 and receiving bevacizumab at the time of implementation of Amendment 4.
Patients in Arm 1, Chemotherapy Treatment Period not receiving bevacizumab when
Amendment 4 is implemented, may continue the 6 cycles of chemotherapy.
Following completion of the Chemotherapy Treatment Period and confirmation of
adequate hematologic parameters, those patients may start niraparib maintenance
therapy as *post-study anticancer treatment* at the Investigator*s discretion.
Patients in Arm 1, Maintenance Treatment Period not receiving bevacizumab when
Amendment 4 is implemented may start niraparib maintenance therapy as
"post-study anticancer treatment" if the time after Cycle 6 Day1 of the
Chemotherapy Treatment Period is <=12 weeks. Patients will be permitted to
remain on study until disease progression, toxicity, or withdrawal from study.
Patients who do not elect to receive niraparib or bevacizumab maintenance will
be discontinued from the study treatment and given the option to stay in the
study for follow up. Investigators will be unblinded for those patients
enrolled in Arm 1 and not receiving bevacizumab at the time of implementation
of Amendment 4.
In total, approximately 1333 patients will be randomized. The study started
with a 1:1:2 randomization ratio. Arm 1 BRCAmut patient enrollment was
stopped after Amendment 2. Arm 1 BCRAwt patient enrollment will stop after
implementation of Amendment 4. It is estimated that approximately 193
patients will have been randomized to Arm 1. At the end of study enrollment,
approximately 1140 patients will be randomized in a 1:2 ratio to Arm 2 or Arm 3
of the study.
Intervention
Pre-Screening Period
During the Pre-Screening Period, patients may sign a pre-screening informed
consent form consenting to collection of the required tumor tissue sample (a
minimum of 1 formalin fixed paraffin embedded [FFPE] block or slides) and the
circulating tumor deoxyribonucleic acid (ctDNA) HRR blood sample required for
randomization. The blood sample for central gBRCA is required. The
Pre-Screening Period can take place within the 14 days prior to the Screening
Period, defined as the date of signing the main informed consent, but does not
have to encompass the full period. A patient can move to the Screening Period
once deemed able.
Screening Period
During the Screening Period, patients will sign the main consent form and
complete all assessments required to determine eligibility into the study. The
Screening Period is within 28 days prior to Cycle 1 Day 1 (C1D1) of the
Chemotherapy Run-In Period.
Chemotherapy Run-In Period (Cycle 1)
Prior to randomization, all patients will receive 1 cycle of
paclitaxel-carboplatin during a Chemotherapy Run-In Period. Patients may also
receive bevacizumab with paclitaxel-carboplatin as part of SOC per local
practice. However, bevacizumab must not be administered less than 28 days
before or 28 days following major surgery, and post operative incisions must be
fully healed. The determination to use bevacizumab must be made prior to
randomization. Patients will be randomized following Cycle 1, prior to
treatment in Cycle 2 during the Chemotherapy Treatment Period. Randomization
may occur up to one week prior to Cycle 2 Day 1.
Intraperitoneal (IP) chemotherapy and weekly paclitaxel will not be allowed.
Chemotherapy Treatment Period (Cycles 2 to 6)
Prior to chemotherapy administration of Cycle 2, all of the following criteria
must be met:
• Absolute neutrophil count (ANC) >=1,500 cells/µL, or >=1000 cells µL if
granulocyte-colony stimulating factor (G-CSF) is to be administered
• Platelet count >=100,000 cells/µL
• Hemoglobin >= 8 g/dL
Thereafter, retreatment criteria for remaining chemotherapy Cycles 3 to 6
should be in accordance to SOC per local practice.
Following randomization, patients who have inoperable disease or who have
undergone PDS will receive cycles 2 to 6 of paclitaxel carboplatin, for a total
of 6 cycles of chemotherapy inclusive of Cycle 1. Patients will also receive
dostarlimab/placebo in combination with paclitaxel-carboplatin started with
Cycle 2 of chemotherapy, for a total 5 cycles. Bevacizumab may continue per
local practice.
Patients for whom NACT is planned will receive 3 to 4 cycles of paclitaxel
carboplatin prior to interval debulking surgery (inclusive of Cycle 1) and 2 to
3 additional cycles of paclitaxel carboplatin following surgery for a maximum
of 6 cycles of chemotherapy that cannot be extended. Interval debulking surgery
cannot occur after 6 cycles of chemotherapy without prior discussion with the
Sponsor. These patients will also receive dostarlimab/placebo, which will be
started with Cycle 2 of chemotherapy, for a total of 5 cycles. Chemotherapy and
dostarlimab/placebo will resume upon recovery of surgery. Patients for whom
NACT is planned may receive bevacizumab with paclitaxel-carboplatin per local
practice as SOC; however, bevacizumab must not be administered less than 28
days before or 28 days following major surgery, and post operative incisions
must be fully healed.
IP chemotherapy and weekly paclitaxel will not be allowed.
Maintenance Treatment Period
Patients who complete the Chemotherapy Treatment Period without progressive
disease (PD) will start the Maintenance Treatment Period after Cycle 6 Day 1.
Dostarlimab/placebo ± bevacizumab will also continue in the Maintenance
Treatment Period in combination with oral maintenance treatment, per study
schedule. However, the start of niraparib will be delayed at least 6 weeks
after Cycle 6 Day 1 and up to 9 weeks after to allow for adequate recovery of
hematologic toxicity.
Prior to starting the first dose of oral niraparib maintenance treatment,
patients must have a complete blood count (CBC) that demonstrate adequate
recovery from hematologic toxicity from chemotherapy:
• Absolute neutrophil count >=1,500 cells/µL
• Platelet count >=100,000/µL
• Hemoglobin >=9 g/dL
• Blood pressure <150/100 mmHg
Weekly CBC is to be performed for the first 4 weeks from the start of niraparib
in the Maintenance Treatment Period.
The recommended SOC order is provided below, unless local clinical practice or
institutional policies differ:
• During the Chemotherapy Treatment Period, dostarlimab/placebo will be
administered first, followed by bevacizumab, then paclitaxel, and lastly
carboplatin.
• During the Maintenance Treatment Period, dostarlimab/placebo will be
administered first, followed by bevacizumab, and then niraparib.
Study burden and risks
NIRAPARIB
Niraparib side effects experienced by patients taking niraparib as a single
drug therapy:
These side effects are common (occur in 1 in 10 people or more)
Decrease in a type of blood cells called platelets that help stop bleeding;
this may increase the risk of bleeding (thrombocytopenia)
Pain or burning when urinating which may indicate an infection (urinary tract
infection)
Decrease in red blood cells that carry oxygen; this may make patients feel
tired or short of breath (anemia)
Feeling tired, lack of energy (asthenia/fatigue)
Decrease in a type of white blood cells called neutrophils that fight
infection; this may decrease the ability to fight infections and may also be
associated with fever, and may lead to a potentially life-threatening condition
caused by the body's response to an infection, triggering changes that can
damage multiple organ systems (neutropenia, neutropenic infection, febrile
neutropenia, neutropenic sepsis)
Headache
Difficulty with emptying the bowels, often because of hard stools
(constipation)
Back pain
Feeling sick to the stomach (nausea)
Joint pain (arthralgia)
Vomiting
Breathlessness or difficulty breathing (dyspnea)
Reduced desire to eat (decreased appetite)
Common cold (nasopharyngitis)
Pain in belly (abdominal pain)
Increased blood pressure (hypertension)
Frequent watery stools (diarrhea)
Feeling lightheaded or like patient is about to faint (dizziness)
Indigestion (dyspepsia)
Cough
Sleeplessness, trouble sleeping (insomnia)
Noticeably rapid, strong, or irregular heartbeat (palpitations)
These side effects occur, but not that often (occur in 1 in 100 people or more)
Altered sense of taste: this means that food might taste differently than
patients are used to (dysgeusia)
Rash
Reduced potassium in the blood (hypokalemia)
Muscle pain (myalgia)
An abnormally rapid heart rate (tachycardia)
An accumulation of fluid that causes swelling in the extremities such as lower
legs, hands and feet (peripheral edema)
Dry mouth
Swelling or irritation of the lining of the mouth, throat, esophagus, stomach,
or intestines (mucosal inflammation/mucositis/stomatitis)
Feeling anxious (anxiety)
Increased liver enzyme in the blood; aspartate transaminase (*AST*), alanine
aminotransferase (*ALT*), gamma glutamyl transferase increased (*GGT*), or
alkaline phosphatase (ALP); this may be a sign of damage to liver cells
Mood change to feeling sad/discouraged, listless (depression)
Increased level of creatinine in the blood; this may be a sign of kidney damage
(blood creatinine increase)
Nose bleed (epistaxis)
Decrease in weight
Inflammation of the lining of the airways (bronchitis)
Infection of the white area of the eye (conjunctivitis)
Increased sensitivity of the skin to sunlight (photosensitivity)
These side effects are considered uncommon (may affect up to 1 in 100 people):
Decrease in number of all types of blood cells (pancytopenia)
These side effects are considered rare (may affect 1 or more, but less than 10
out of every 10,000 patients):
A brain condition with symptoms including seizures, headache, confusion and
changes in vision (posterior reversible encephalopathy syndrome [PRES])
Severe increase in blood pressure (hypertensive crisis)
In addition to the above, the side effects below were reported by patients who
were prescribed niraparib by their doctors:
• Allergic reaction (hypersensitivity*, including anaphylaxis**).
• Life-threatening allergic reaction (such as difficulty breathing, rash,
localized swelling, such as tongue, throat or lips) (anaphylaxis*)
• Confusion (confusional state*: symptom that makes you feel as if you can't
think clearly. You might feel disoriented and have a hard time focusing or
making decisions)
• Seeing or hearing things that are not really there (hallucination*)
• Impaired concentration, understanding, memory* and thinking (cognitive
impairment*)
• Inflammation of the lungs which can cause shortness of breath and difficulty
breathing (non-infectious pneumonitis*)
*Observed frequency in clinical trials uncommon (may affect up to 1 in 100
people).
**No events reported in monotherapy clinical trials.
Potential for a new blood cancer, myelodysplastic syndrome and/or acute myeloid
leukemia (MDS/AML), a new primary cancer, embolic and/or thrombotic events
(blood clots):
Niraparib belongs to a group of drugs called PARP inhibitors. This group of
drugs are suspected of causing new blood cancers known as myelodysplastic
syndrome (MDS) and acute myeloid leukemia (AML). Because niraparib is a PARP
inhibitor there is a potential risk of developing a new blood cancer leading to
leukemia.
If patients have had MDS or leukemia before entering this study, they are at
increased risk for developing leukemia again.
Although rare, patients in niraparib clinical trials have had MDS/AML. In
another study in recurrent ovarian cancer patients, MDS/AML was not more common
in patients receiving niraparib than in patients receiving placebo.
PARP inhibitors may also cause a new primary cancer.
Blood clotting (venous thrombosis) has been noted in ovarian cancer patients
with and without use of niraparib. This may cause symptoms such as swelling,
pain, warmth and redness in your legs or elsewhere. Clotting in the lungs may
cause trouble breathing, cough and rapid heartbeat.
Niraparib capsules contain tartrazine which may cause allergic-type reactions.
DOSTARLIMAB
Dostarlimab side effects experienced by patients taking Dostarlimab as a single
drug therapy:
These side effects are very common (occur in 1 in 10 people or more)
Decrease in the number of red blood cells that carry oxygen. Low red blood
cells count may make you feel tired or short of breath and symptoms may require
a blood transfusion (anaemia)
Feeling sick to the stomach (nausea)
Vomiting
Loose/liquid stools (diarrhoea)
Itchy skin (pruritus)
Rash
Increased levels of substances in the blood produced by the liver which may be
a sign of liver injury (AST increased, ALT increased) (transaminases increased)
These side effects are common (occur in more than 1 people in 100, but less
than 10 people in 100)
Decreased production of adrenal hormones resulting in possible weakness and/or
low blood pressure (adrenal insufficiency)
Underactive thyroid gland (hypothyroidism)
Overactive thyroid gland (hyperthyroidism)
Inflammation of the lungs which can cause shortness of breath and difficulty
breathing (pneumonitis)
Inflammation of the colon that can cause stomach pain or diarrhea (colitis)
Muscle pain (myalgia)
Chills
Fever (pyrexia)
Infusion-related reaction which can occur within 24 hours after receiving an
intravenous infusion, or which can be delayed for up to about 2 weeks.
Infusion-related reactions may include dizziness or fainting, flushing, rash,
fever, chills, shortness of breath, increased or decreased blood pressure,
increased heart rate, swelling of the lips, tongue or face, feeling sick to
your stomach, back pain or pain at the site of infusion. Although
infusion-related reactions are usually reversible, they can be severe or life
threatening. (infusion related reactions)
There are rare but serious immune-related adverse events which have been seen
when dostarlimab was used in combination with other medicines:
Inflammation of the muscle which can cause weakness, swelling and pain
(myositis)
Inflammation throughout the whole body leading to high or low temperatures, low
blood pressure, increased heart rate, increased rate of breathing and low or
high white blood cell count (systemic inflammatory response syndrome)
Overactive immune-system cells which can damage body tissues and organs leading
to signs of uncontrolled fever, enlarged spleen, low blood count and liver test
abnormalities. This disease can be fatal. (hemophagocytic lymphohistiocytosis)
UNFORESEEABLE RISKS
When Study Drugs are taken alone or in combination with other medic
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Age
Inclusion criteria
To be considered eligible to participate in this study, all of the following
requirements must be met:
1. Patients must be female, >=18 years of age, able to understand the study
procedures, and agree to participate in the study by providing written informed
consent.
2. Patients with a histologically confirmed diagnosis of high-grade
nonmucinous epithelial ovarian (serous, endometrioid, clear cell,
carcinosarcoma, and mixed pathologies), fallopian tube, or primary peritoneal
cancer that is Stage III or IV according to the International Federation of
Gynecology and Obstetrics or tumor, node and metastasis staging criteria [ie,
American Joint Committee on Cancer].
3. All patients with Stage IV disease are eligible. This includes those with
inoperable disease, those who undergo PDS (CC0 or macroscopic disease), or
those for whom NACT is planned.
4. Patients with Stage III are eligible if they meet one or more of the
following criteria:
a. Stage IIIC patients with CC0 resection if they meet the following criteria:
aggregate >=5 cm extra-pelvic disease during PDS as assessed by the Investigator
b. All patients with inoperable Stage III disease
c. All Stage III patients with macroscopic residual tumor (per Investigator
judgment) following PDS
d. All Stage III patients for whom NACT is planned.
5. Patient must provide a blood sample for ctDNA HRR testing at Pre-Screening
or Screening.
6. Patient must provide sufficient tumor tissue sample (a minimum of 1 FFPE
block or slide at Pre-Screening or Screening for PD-L1, homologous
recombination deficiency HRD testing.
7. Patients of childbearing potential must have a negative serum or urine
pregnancy test (beta human chorionic gonadotropin) within 3 days prior to
receiving the first dose of study treatment.
8. Patients must be postmenopausal, free from menses for >1 year, surgically
sterilized, or willing to use highly effective contraception to prevent
pregnancy or must agree to abstain from activities that could result in
pregnancy throughout the study, starting with enrollment through 180 days after
the last dose of study treatment.
9. Patients must have adequate organ function, defined as follows (Note: CBC
test should be obtained without transfusion or receipt of stimulating factors
within 2 weeks before obtaining Screening blood sample):
a. Absolute neutrophil count >=1,500/µL
b. Platelet count >=100,000/µL
c. Hemoglobin >=9 g/dL
d. Serum creatinine <=1.5 × upper limit of normal (ULN) or calculated creatinine
clearance >=60 mL/min using the Cockcroft-Gault equation
e. Total bilirubin <=1.5 × ULN or direct bilirubin <=1.5 × ULN
f. Aspartate aminotransferase and alanine aminotransferase (ALT) <=2.5 × ULN
unless liver metastases are present, in which case they must be <=5 × ULN
10. Patients must have an ECOG score of 0 or 1.
11. Patients must have normal blood pressure (BP) or adequately treated and
controlled hypertension (systolic BP <=140 mmHg and/or diastolic BP <=90 mmHg).
12. Patients must agree to complete HRQoL questionnaires throughout the study.
13. Patients must be able to take oral medication.
Exclusion criteria
Patients will not be eligible for study entry if any of the following criteria
are met:
1. Patient has mucinous, germ cell, transitional cell, or undifferentiated
tumor.
2. Patient has low grade or Grade 1 epithelial ovarian cancer.
3. Stage III patient with R0 resection after PDS (ie, no macroscopic residual
disease, unless inclusion criterion #4a is met).
4. Patient has not adequately recovered from prior major surgery.
5. Patient has a known condition, therapy, or laboratory abnormality that might
confound the study results or interfere with the patient*s participation for
the full duration of the study treatment in the opinion of the Investigator.
6. Patient is pregnant or is expecting to conceive children while receiving
study drug or for up to 180 days after the last dose of study drug. Patient is
breastfeeding or is expecting to breastfeed within 30 days of receiving the
final dose of study drug (women should not breastfeed or store breastmilk for
use, during niraparib treatment and for 30 days after receiving the final dose
of study treatment).
7. Patient has known active central nervous system metastases, carcinomatous
meningitis, or both.
8. Patient has clinically significant cardiovascular disease (eg, significant
cardiac conduction abnormalities, uncontrolled hypertension, myocardial
infarction, uncontrolled cardiac arrhythmia or unstable angina <6 months to
enrollment, New York Heart Association Grade 2 or greater congestive heart
failure, serious cardiac arrhythmia requiring medication, Grade 2 or greater
peripheral vascular disease, and history of cerebrovascular accident within 6
months).
9. Patient has a bowel obstruction by clinical symptoms or CT scan,
subocclusive mesenteric disease, abdominal or gastrointestinal fistula,
gastrointestinal perforation, or intra abdominal abscess.
10. Patient initiating bevacizumab as SOC has proteinuria as demonstrated by
urine protein:creatinine ratio >=1.0 at Screening or urine dipstick for
proteinuria >=2 (patients discovered to have >=2 proteinuria on dipstick at
baseline should undergo a 24 hour urine collection and must demonstrate <2 g of
protein in 24 hours to be eligible).
11. Patient has any known history or current diagnosis of MDS or AML.
12. Patient has been diagnosed and/or treated with any therapy for invasive
cancer <5 years from study enrollment, completed adjuvant chemotherapy and/or
targeted therapy (eg, trastuzumab) less than 3 years from enrollment, or
completed adjuvant hormonal therapy less than 4 weeks from enrollment. Patients
with definitively treated noninvasive malignancies such as cervical carcinoma
in situ, ductal carcinoma in situ, Grade 1 or 2, Stage I endometrial cancer, or
non -melanomatous skin cancer are allowed.
13. Patient is at increased bleeding risk due to concurrent conditions (eg,
major injuries or major surgery within the past 28 days prior to start of study
treatment and/or history of hemorrhagic stroke, transient ischemic attack,
subarachnoid hemorrhage, or clinically significant hemorrhage within the past 3
months).
14. Patient is immunocompromised. Patients with splenectomy are allowed.
Patients with known human immunodeficiency virus (HIV) are allowed if they meet
all of the following criteria:
a. Cluster of differentiation 4 >=350/µL and viral load <400 copies/mL
b. No history of acquired immunodeficiency syndrome-defining opportunistic
infections within 12 months prior to enrollment
c. No history of HIV associated malignancy for the past 5 years
d. Concurrent antiretroviral therapy as per the most current National
Institutes of Health (NIH) Guidelines for the Use of Antiretroviral Agents in
Adults and Adolescents Living with HIV started >4 weeks prior to study
enrollment
15. Patient has known active hepatitis B (eg, hepatitis B surface antigen
reactive) or hepatitis C (eg, hepatitis C virus ribonucleic acid [qualitative]
is detected).
16. Patient is considered a poor medical risk due to a serious, uncontrolled
medical disorder, nonmalignant systemic disease, or uncontrolled infection.
Specific examples include, but are not limited to, history of non-infectious
pneumonitis that required steroids, current pneumonitis, uncontrolled
autoimmune disease, uncontrolled ventricular arrhythmia, recent myocardial
infarction within 90 days of consent, uncontrolled major seizure disorder,
unstable spinal cord compression, superior vena cava syndrome, or any
psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the study (including obtaining informed consent).
17. Patient has had investigational therapy administered within 4 weeks or
within a time interval less than at least 5 half lives of the investigational
agent, whichever is longer, prior to the first scheduled day of dosing in this
study.
18. Patient has received a live vaccine within 14 days of planned start of
study therapy. Seasonal influenza vaccines that do not contain live viruses are
allowed.
19. Patient has a known contraindication or uncontrolled hypersensitivity to
the components of paclitaxel, carboplatin, niraparib, bevacizumab, dostarlimab,
or their excipients.
20. Prior treatment for high-grade nonmucinous epithelial ovarian, fallopian
tube, or peritoneal cancer (immunotherapy, anticancer therapy, radiation
therapy).
21. Patient has an active autoimmune disease that has required systemic
treatment in the past 2 years. Replacement therapy is not considered a form of
systemic therapy (eg, thyroid hormone or insulin).
22. Patient has a diagnosis of immunodeficiency or is receiving systemic
steroid therapy or any other form of systemic immunosuppressive therapy within
7 days prior to the first dose of study treatment.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-510605-28-00 |
| EudraCT | EUCTR2018-000413-20-NL |
| CCMO | NL66122.042.18 |