Primary: To characterize the safety and tolerability of PDR001 in combination with LCL161, everolimus, HDM201, QBM076 or panobinostat and to identify recommended doses and schedules for future studies.Secondary: To characterize changes in the immune…
ID
Source
Brief title
Condition
- Other condition
- Breast neoplasms malignant and unspecified (incl nipple)
- Respiratory tract neoplasms
Synonym
Health condition
colorectaal kanker (muv mismatch repair deficienties), non-small cell long kanker (adenocarcinoma) en triple negatieve borstkanker
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Adverse events, dose limiting toxicities, dose interruptions and reductions,
dose intensities.
Secondary outcome
Tumor infiltrating lymophocytes, ECGs, Best overall response, treatment free
survival, PK parameters, anti-PDR001 antibodies.
Background summary
PDR001 is a high-affinity, ligand-blocking, humanized anti-PD-1 IgG4 antibody
that blocks the binding of PD-L1 and PD-L2 to PD-1. PDR001 shows functional
activity in vitro/ex vivo. The first in human study is ongoing. By the end of
December 2015, a total of 58 patients had been treated in the study at the dose
levels of 1, 3 and 10 mg/kg every 2 weeks and 3 and 5 mg/kg every 4 weeks. No
patient experienced a dose limiting toxicity and the toxicity profile appears
to be similar to that of marketed inhibitors of PD-1. The PK data support the
use of flat dosing for PDR001 of 400 mg every 4 weeks.
Agents that enhance anti-tumor immunity are not effective in all cancer types,
responses are often not durable, and many patients receive little or no benefit
from treatment. Inhibitors of the PD-1/PD-L1 interaction are well tolerated and
active across a range of cancer types, and will likely be one component of
combination therapies that increase the response rate and durability of
treatment.
The agents to be combined with PDR001 in this trial are used as
immunomodulators, not as direct anti-tumor agents. The marketed agents,
panobinostat and everolimus, will be used in indications where they are not
approved, and in the case of everolimus will be administered at a significantly
lower dose and less frequently than in the approved regimen. The goal is to use
these agents to stimulate a more effective anti-tumor immune response, not as
inhibitors of critical pathways that tumor cells depend upon for survival. For
these reasons, and because enhancing the antitumor immune response is expected
to be beneficial across many diseases, these combinations will be tested in
indications that are different from those in which they are marketed.
• PDR001 in combination with LCL161. LCL161, an investigational IAP inhibitor
that targets components of the TNF receptor complex and induces immune
activation, for which there is preliminary clinical evidence of activity in
TNBC (triple-negative breast cancer), and which enhances antitumor activity in
preclinical models in combination with a PD-1 inhibitor.
• PDR001 in combination with everolimus. Everolimus, a marketed inhibitor of
mTOR that enhanced T cell function and increased influenza titers when given at
low dose prior to vaccination in elderly subjects
• PDR001 in combination with panobinostat. Panobinostat, a marketed HDAC
inhibitor that enhances antitumor activity in preclinical models in combination
with a PD-1 inhibitor.
• PDR001 in combination with HDM201 . HDM201 inhibits the interaction between
TP53 and HDM2, preventing tumorgrowth
• PDR001 in combinatie met QBM076. QBM076 is an antagonist of CXCR2 receptor,
due to which inhibition of immunoregulated antitumorrespons is prevented
The study will identify the doses and schedule for further testing and will
preliminarily assess the safety, tolerability, pharmacological and clinical
activity of these combinations.
Four cancer types have been chosen for study:
• CRC (colorectal cancer): a cancer in which PD-1/PD-L1 therapy is ineffective
for unknown reasons. Published data suggest that the immune context in tumors
is prognostic and predictive of response to treatment with conventional
chemotherapy, but for unknown reasons PD-1 or CTLA-4 inhibitors are
ineffective). The purpose of including CRC is to learn whether combination
therapy may activate a more effective anti-tumor response.
• NSCLC (non-small cell lung cancer): a cancer in which PD-1 checkpoint
inhibitors are clinically active and marketed. The activity of PD-1 inhibitors
in this disease is limited to a minority of patients. The purpose of including
NSCLC is to provide a preliminary assessment of whether combination therapy may
broaden activity, deepen responses, or lead to more durable responses.
• TNBC: a cancer with preliminary evidence of limited clinical efficacy with
PD-1/PD-L1 therapy. The purpose of including TNBC is to provide a preliminary
assessment of whether combination therapy may increase the proportion of
patients who respond to treatment.
• TP53 wt RCC: effective treatment by PD1 inhibition has been proven. TP53
positivity is seen in approx. 25 % of all RCC patients.
The purpose of the study is to provide preliminary evidence that a combination
may increase the response rate and durability of response compared with
published data for treatment with single agent PD-1 inhibitors. Each disease
group may include a subset of patients previously treated with PD-1 checkpoint
inhibitors to explore whether combination therapy might overcome resistance to
PD-1 blockade. For each disease, no specific molecular selection will be
applied as the data available at present generally do not support excluding
patients on the basis of approved molecular diagnostic tests such as PD-L1
expression.
The study will also assess whether each combination induces pharmacologic
changes in tumor that would suggest potential clinical benefit, and will
preliminarily assess the efficacy of each combination.
Study objective
Primary:
To characterize the safety and tolerability of PDR001 in combination with
LCL161, everolimus, HDM201, QBM076 or panobinostat and to identify recommended
doses and schedules for future studies.
Secondary:
To characterize changes in the immune infiltrate in tumors. To estimate the
anti-tumor activity. To characterize the pharmacokinetics of all study drugs in
combination. Immunogenicity. Cardiac safety of panobinostat combination with
PDR001
Study design
Multicenter phase Ib open-label dose escalation and dose expansion study of
PDR001 fixed dose (IV 400 mg Q4W) in combination with oral LCL161, everolimus,
HDM201, QBM076 or panobinostat.
The study treatment will be administered during 28-days cycles.
Treatment period 1: 6 cycles; thereafter discontinuation of study treatment
(treatment interruption period). Restart of (same) study treatment in treatment
period 2 in case of progression during treatment interruption period until
disease progression or unacceptable side effects.
Approx. 410 subjects.
Intervention
Treatment with PDR001 IV 400 mg in combination with the following oral
treatments in the following doses:
LCL161:
Start: 300 mg/week,
-1: 300mg/4 weeks,
+1: 900mg/week.
Everolimus:
Start: 5 mg/week,
-1: 0.5mg /day.
Panobinostat:
Start: 10mg 3x/week 1week on/1 week off,
-1: 10mg 3x/week 1week on/3weeks off,
+1: 20mg 3x/week 2weeks on/1 week off.
HDM201
100 mg D1 and D8 during 28 days cycles
QBM076
75 mg BID dyring 2 weken of 28 days cycles
Study burden and risks
Risk: Adverse effects of PDR001 in combination with LCL161, everolimus or
panobinostat. Risk of treatment interruption after first 6 cycles.
Burden: Cycles of 4 weeks. Treatment period 1: Cycle 1: 4 visits, cycle 2-3: 2
visits, cycle 4-6 onwards: 1 visit per cycle. Treatment interruption period:
monthly visits. Treatment period 2: Cycle 1-2: 4 visits, cycle 3 onwards: 1
visit per cycle. Visit duration mostly 1-4 hours.
IV infusions of PDR001 once per 4 weeks (250 ml per occasion). Duration
standard 0,5 hour.
Physical examination: (x in cycle 1, 2 x in cycle 2 and starting cycle 3, 3x
per cycle.
Blood tests (12-36 ml/occasion): all visits.
PK days 6-8 hours duration: once or twice. PK blood volume 12-36 ml/cycle.
Blood for biomarkers: 80 ml in total.
ECG: 1 times in total, in case of treatment with PDR001 plus panobinostat: all
visits, except EOT
2 tumor biopsies (third is optional).
CT-/MRIscan: every 8-12 weeks.
Echocardiography/MUGA-scab: once.
Optional use of the remaining blood and tissue for future research.
Haaksbergweg 16
Amsterdam 1101 BX
NL
Haaksbergweg 16
Amsterdam 1101 BX
NL
Listed location countries
Age
Inclusion criteria
• Female and male patients >= 18 years old.
• Subjects, who have progressed despite standard therapy or are intolerant to
standard therapy, or for whom no standard therapy exists. Diagnosis CRC, NSCLC,
TNBC, TP53 wt CRC and TP53 wt RCC.
See protocol page 39 for details.
• ECOG performance status 0-1.
• Disease amenable to biopsy and a candidate for tumor biopsy according to the
treating institution*s guidelines. Patient must be willing to undergo a new
tumor biopsy at baseline, and during therapy on this study.
• Prior therapy with PD-1/PDL-1 inhibitors is allowed. See protocol page 40 for
details.
Exclusion criteria
• History of severe hypersensitivity reactions to other monoclonal antibodies
(mAbs).
• Patients with known hypersensitivity to any of the components of
investigational treatment will be excluded from participation in the
corresponding arm. Patients that have a history of hypersensitivity to
rapamycin derivatives will be excluded from participation in the everolimus arm
• History of or current drug-induced interstitial lung disease or pneumonitis
grade >=2
• Symptomatic CNS metastases or CNS metastases that require local CNS-directed
therapy or increasing doses of corticosteroids within the prior 2 weeks.
• Out of range laboratory values. See protocol page 40 for details. Impaired
cardiac function or clinically significant cardiac disease. See protocol page
40 for details.
• Active autoimmune disease, infection requiring antibiotics.
• HBV or HCV infection. Known HIV infection. See protocol page 41 for details.
• Systemic anti-cancer therapy within 2 weeks of the first dose of study
treatment. See protocol page 41 for details.
• Treatment with systemic steroid therapy, other than in the setting of adrenal
insufficiency, systemic immunosuppressive therapy.
• Life vaccines against infectious diseases within 4 weeks of initiation of
study treatment.
• Major surgery within 2 weeks. See protocol page 41 for details.
• Radiotherapy within 2 weeks, except for palliative radiotherapy to a limited
field.
• CSF within 3 weeks. See protocol page 41 for details.
• Pregnancy, lactation, insufficient contraception for females of childbearing
potential.
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 | EUCTR2016-000654-35-NL |
| ClinicalTrials.gov | NCT02404441 |
| CCMO | NL57900.041.16 |