The primary objective is to determine the safety, tolerability, dose-limiting toxicities (DLTs), and maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of BMS-986178 administered alone or in combination with nivolumab and/or ipilimumab in…
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During the Dose Escalation phase the following tumor histologies permitted except primary CNS tumors; Melanoma, NSCLC, Head and neck, Transitional cell carcinoma of the genitourinary tract, Renal cell carcinoma, Pancreatic adenocarcinoma, Colorectal cancer, Cervical cancer, Triple negative breast cancer, Adenocarcinoma of the endometrium, Ovarian cancer, Prostate adenocarcinoma, Hepatocellular cancer-Child Pugh A only, Small cell lung cancer, Gastric and gastric esophageal junction cancer. Dose Expansion, Safety cohort and schedule and dose exploration:Melanoma, NSCLC, Head and neck cancer, Transitional cell carcinoma of the genitourinary tract, Renal cell carcinoma, Pancreatic adenocarcinoma, CRC, Cervical cancer, Triple negative breast cancer, Adenocarcinoma of the endometrium, Ovarian cancer, Prostate adenocarcinoma, Hepatocellular cancer, Small cell lung cancer, Gastric and gastric esophageal junction cancer, Bladder cancer and Thyroid cancer.
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety:
The primary endpoint of this Phase I / IIa study's safety as measured using
extensive medical assessment of adverse events (AEs), vital signs (blood
pressure etc), ECGs, physical examination, and clinical significant laboratory
abnormalities. Side effects are continuously monitored during the investigation
and 100 days after the last treatment. Reported side effects will be further
analysed significance and clinical importance.
Secondary outcome
Efficacy:
Anti-tumour activity is monitored by means of CT / MRI during screening and
every 8 weeks until disease progression. When disease progression occurs, there
is no need more scans to be performed unless there are by treated (by treatment
after disease progression). In this case, every 12 weeks, scans are carried out
to there again stops until disease progression or the treatment. Consideration
will be given to overall survival, duration of response and progression-free
survival at 24 weeks.
pharmacokinetics:
Selected PK parameters such as Cmax, Tmax, AUC () - t), AUC (TAU) will be
determined in two cycles depending on the scheduling of mono- or combination
therapy. Parameters such as Ctau, CLT, Css-avg, accumulation index (AI), and
effective elimination half-life (THALFeff) will be assessed in the second cycle
when intensive PK are collected. A separate listing, summary, and plot will be
generated for Ctrough.
immunogenicity:
This consists of collection of serum samples to the development of specific
antibodies (ADA's) in response to research tool (s) to evaluate BMS-986 178 and
nivolumab or ipilimumab. Blood samples will be collected at several intervals.
Exploratory biomarkers:
Overall survival rate will be determined at a fixed time and the number of
patients who are still alive at that time.
Overall survival is defined as the time between the first dose and date of
death from any cause.
Analyses of biomarkers of samples obtained at baseline and during treatment
from peripheral blood, serum and tumour biopsy to study markers of
pharmacodynamics. Additional research is to investigate the hypothesis related
to mechanisms, biomarkers for safety and biomarkers that predict what the
response will be to treatment with BMS-986 178 as monotherapy or in combination
with nivolumab and/ or ipilimumab.
Background summary
Immunotherapy for cancer has become established in recent years and is now one
of the most successful and important strategies for treating patients with
haematological malignancies and solid tumours.
The most extensively studied immunotherapies in cancer are the negative
regulatory receptors, CTLA-4, and PD-1. Following the success of CTLA-4 and
anti-PD-1 pathway-targeted agents in several cancers, the field of tumour
immunotherapy is rapidly expanding. In addition to blocking co-inhibitory
pathways, activating co-stimulatory pathways to potentiate anti-tumour immune
responses is being considered as a promising approach. Members of the tumour
necrosis factor receptor super family (TNFRsf) include several co-stimulatory
proteins with key roles in B- and T-cell development, survival, immune
activation, and anti-tumour immune responses. Preclinical data have provided
the basis for the trial of agonist antibodies to TNFRsf co-stimulatory
receptors as potential therapies for patients with cancer. Overall, enhancement
of the magnitude and potency of tumour antigen-specific adaptive cellular
responses by CD8 and CD4 T-cells is now considered a major goal in cancer
immunotherapy.
With these recent emerging clinical lines of evidence of significant activity
of single-agent immunotherapies, combination therapies could potentially lead
to greater depth of response and OS, as has been noted with the combination of
anti-PD-1 and anti-CTLA-4 in advanced melanoma patients.
BMS-986178 is an anti-OX40 agonist mAb under exploration as a treatment for
advanced malignancies. Nivolumab is an anti-programmed cell death-1 (PD-1)
monoclonal antibody (mAb) approved for the treatment of metastatic melanoma,
non-small cell lung cancer (NSCLC), and advanced renal cell carcinoma (RCC) in
multiple countries, and Ipilimumab is an anti-cytotoxic T-lymphocyte associated
antigen-4 (CTLA-4) mAb approved for the treatment of metastatic melanoma in
multiple countries.
The proposed clinical study, CA012004, is a Phase 1/2a dose escalation and dose
expansion study of BMS-986178 in monotherapy and in combination with nivolumab
or/and ipilimumab in patients with advanced solid tumours. It is the first
study of BMS-986178 in humans. This study will evaluate the safety profile,
tolerability, preliminary efficacy, PK, and PD of intravenous (IV) doses of
BMS-986178 administered as monotherapy and in combination with nivolumab or/and
ipilimumab in patients with advanced solid tumours. This study will also
determine the maximum tolerated dose (MTD) and RP2D of BMS-986178 to be
used in future monotherapy and in combination with nivolumab or/and ipilimumab.
Study objective
The primary objective is to determine the safety, tolerability, dose-limiting
toxicities (DLTs), and maximum tolerated dose (MTD)/recommended Phase 2 dose
(RP2D) of BMS-986178 administered alone or in combination with nivolumab and/or
ipilimumab in patients with advanced solid tumours.
The secondary objectives are;
• To investigate the preliminary anti-tumour activity of BMS-986178
administered alone or in combination with nivolumab and/or ipilimumab in
patients with advanced solid tumours
• To characterise the pharmacokinetics (PK) of BMS-986178 administered alone or
in combination with nivolumab and/or ipilimumab
• To characterise the immunogenicity of BMS-986178 administered alone or in
combination with nivolumab and/or ipilimumab and the immunogenicity of
nivolumab or ipilimumab administered with BMS-986178
The exploratory objectives are:
• To explore potential associations between anti-tumor activity and select
biomarker measures in tumor biopsy specimens and peripheral blood prior to
treatment and following administration of BMS-986178 alone or in combination
with nivolumab and/or ipilimumab
• To assess the potential effect of BMS-986178 monotherapy and combination
therapy on QTc interval
• To characterize nivolumab PK in subjects receiving the combination of
nivolumab and BMS-986178 or the combination of nivolumab, ipilimumab, and
BMS-986178
• To characterize ipilimumab PK in subjects receiving the combination of
ipilimumab and BMS-986178 or the combination of nivolumab, ipilimumab, and
BMS-986178
• To assess the overall survival (OS) in subjects treated with BMS-986178 alone
andor in combination with nivolumab and/or ipilimumab
Study design
This is a Phase I / IIa, open-label study of BMS-986 178 administered as
monotherapy or in combination with ipilimumab or/and nivolumab in patients with
advanced solid tumours.
The research is conducted in 4 parts. Part 1 (dose escalation) has 3 groups,
Part 2 (dose expansion) has 4 groups, Part 3 (schedule and dose exploration)
has 2 groups and Part 4 (safety cohort) has 2 groups.
Part 1 is the escalation phase and represents the phase I of this study. It has
3 treatment groups (Group A, B and C).
In group A, patients have received increasingly higher doses treated with
monotherapy BMS-986 178. The clinical data that come from the first 3 dosage
levels, have formed the basis for the dose of BMS-986178 which was administered
in combination with nivolumab and was given in increasingly higher doses in
patients in Group B. Subsequently, the clinical data composed of both group A
and group B formed the basis for the pre-dose of BMS-986178 which was
administered in combination with ipilimumab also in increasingly higher doses
in patients in group C. Phase 1 is now complete.
The expansion dose (Part 2), the schedule and dose exploration cohort (Part 3)
and the safety cohort (Part 4) represent the phase IIa of this study.
After Part 1 established the maximum tolerated dose and recommended dose for
Part 2, this dose will be launched in a select group of tumours. This selected
group of tumour types consists of cervix, colorectal, bladder, ovarian, renal
cell, non small cell lung cancer, and other signal seeking cancers. Patients
with colorectal, bladder, cervical or other signal seeking tumours will be
treated with BMS-986 178 + nivolumab. Patients with ovarian cancer or other
signal seeking tumours will be treated with BMS-986 178 + ipilimumab. Patients
with renal cell cancer or with non-small cell lung cancer will be treated with
BMS-986178 in combination with Nivolumab and Ipilimumab.
In the schedule and dose exploration (Part 3), patients with cervix,
colorectal, bladder, cancer or other signal seeking tumours, will receive
Nivolumab in combination BMS-986178. Patients with ovarian cancer or other
signal seeking tumours will be treated with ipilimumab in combination
BMS-986178. The tested doses of Nivolumab and ipilimumab will be higher than
the ones tested in the dose escalation and the dose expansion parts. The tested
dose of BMS-986178 will be a dose that has been found to safe in Part 1.
In the safety cohort (Part 4), patients with renal cell cancer or non-small
cell lung cancer will be treated with BMS986-178 in combination with Ipilimumab
and Nivolumab.
Intervention
Group A, every two weeks, 24 weeks
Dose Level 1: 20 mg
Dose Level 2: 40 mg
Dose Level 3: 80 mg
Dose Level 4: 160 mg
Dose Level 5: 320 mg
Group B, every 2 weeks, 24 weeks. 3 dosage level BMS-986178 is based on the
results of the first three dose level BMS-986178 from group A.
Test patients in this group will also, every two weeks, are treated with 240 mg
(intravenously) Nivolumab.
Group C, every 3 weeks, 24 weeks. 3 dosage level BMS-986178 is based on the
results of the first three dose level BMS-986178 of group A and group B.
Test patients in this group will also, every three weeks, are treated with 1 mg
/ kg (intravenously) ipilimumab. A maximum of 4x ipilimumab is given, then is
BMS-986178 administered as monotherapy to 24 weeks.
Patients in the expansion phase will be treated with the MTD, MAD, or an
alternative dose of BMS-986178 in combination with nivolumab (groups 2B, 2C. 2D
or 2E), with ipilimumab (groups 3B or 3C) or nivolumab with ipilimumab (groups
6B and 7B), as agreed with the sponsor and investigators. For Groups 2B-2E,
Nivolumab will be administered in a fixed dose of 240 mg. For Groups 3B-3C,
ipilimumab will be administered at a dose of 1 mg / kg.
Patients in Group 6B will receive 40 mg of BMS986-178 with 240 mg of nivolumab
and ipilimumab at 1 mg/kg every 3 weeks for 4 cycles. They will then receive
BMS-986178 (40 mg) and nivolumab (480 mg) every 4 weeks for 3 cycles, as a
maintenance therapy. Patients in Group 7B will receive 40 mg of BMS-986178 will
be administered at a flat dose of 40 mg and a flat dose of 240 mg of nivolumab
every 2 weeks and ipilimumab , at 1 mg/kg; every 6 weeks for 4 cycles.
Patients in the safety cohort will receive the same treatment as patients in
Groups 6B and 7B.
Patients in the schedule and dose exploration (Groups 4 and 5) will receive a
dose BMS986-178 that has been shown to be safe in Group B in combination with
480 mg of nivolumab every 4 weeks.
Patients in the safety cohort (Groups 6A and 7A) will receive the same
treatment as patents in Groups 6B and 7B.
The doses of ipilimumab and nivolumab cannot be adjusted. Courses and duration
of treatment is the same in all groups so two-weekly for BMS-986 178 as
monotherapy or in combination with nivolumab, 3-week BMS-986 178 when combined
with ipilimumab alone, or 4 weekly for Group 6B and 6-weekly for Group 7B.
Study burden and risks
Patients are expected in the research to repeatedly visit the hospital for
physical examination, measurement of vital signs, routine blood test for
assessing safety, pregnancy test (for women of childbearing potential) and
control side effects. In addition, the tumours of the patients will be assessed
every 8 weeks radiographically (with CT or MRI scan) until progression of the
disease or if patients stop the treatments. Patients will have to undergo
mandatory biopsies before and during treatment. On some visits blood will be
drawn for scientific purposes (pharmacokinetics, pharmacodynamics,
immunogenicity and biomarkers). The frequency of the visits, and the number of
procedures that is run during this study, is generally more than with the
standard treatment. Patients will be instructed to contact directly with the
research / physician if they experience side effects. They also get a patient
emergency card along with all the necessary study information (emergency
number, etc.)
Uxbridge business Park Uxbridge business Park
Uxbridge UB8 1DH
GB
Uxbridge business Park Uxbridge business Park
Uxbridge UB8 1DH
GB
Listed location countries
Age
Inclusion criteria
• Patients must have at least 1 standard treatment regimen in the advanced, recurrent or metastatic setting;• ECOG (Eastern Cooperative Oncology Group) 0-1;• Men and women 18 years old or older;• At least one measurable lesion at baseline by CT (computed tomography) or MRI (magnetic resonance imaging) as per RECIST (Response Evaluation Criteria In Solid Tumors) v1.1
Exclusion criteria
• Known central nervous system metastases or central nervous system as the only source of disease;• Concomitant malignancies;• Active known or suspected autoimmune disease;• Uncontrolled or significant cardiovascular disease;• Major surgery less than 4 weeks before the start of the study
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 |
|---|---|
| EudraCT | EUCTR2015-004816-39-NL |
| ClinicalTrials.gov | NCT02737475 |
| CCMO | NL57826.031.16 |