Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT01952769 |
| Other study ID # |
antiPD1brainad2- HMO-CTIL |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
Phase 1/Phase 2
|
| First received |
September 15, 2013 |
| Last updated |
September 11, 2016 |
| Start date |
February 2014 |
| Est. completion date |
April 2019 |
Study information
| Verified date |
October 2015 |
| Source |
Hadassah Medical Organization |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Israel : Ministry of Health - Director General |
| Study type |
Interventional
|
Clinical Trial Summary
Diffuse pontine gliomas are incurable with currently used treatments. based on data stating
that progressive tumors inhibit immune system, would try to enhance immune system activity
and tumor cell killing. anti PD1 prevents one of the important mechanisms allowing the tumor
to supress the immune system thus we hope it will allow for prolonged control of the tumors
Description:
1. Diffuse intrinsic pontine glioma Diffuse intrinsic pontine glioma (DIPG) is the most
lethal pediatric malignant disease. Children are usually diagnosed at the age of 6-8
years following a short history of neurological deterioration with often a combination
of cranial nerve dysfunction, ataxia and long tract deficits. Diagnosis is MRI based
and a biopsy is required only when tumor features on imaging are non-classic . As of
today there is no curative treatment regardless of multiple clinical trials done in the
past. Following diagnosis children undergo radiation therapy aiming at symptoms
alleviation, with almost inevitable disease progression taking place several months
later. Overall survival ranges between 9-12 months and death due to disease progression
is the rule (1)
2. Relapsed high grade glioma- closed to accrual
3. Immunotherapy in brain tumors Data regarding possible role of the immune system in
cancer was first presented in 2001 when Schreiber and Old demonstrated that
lymphocytes, activated by interferon-γ, inhibit the development of spontaneous and
carcinogen-induced tumors in immunodeficient mice (Shankaran et al, 2001). Later
studies demonstrated progressively decreasing immunogenicity in tumor cells of advanced
cancer patients. Based on these and other data trials incorporating immunotherapy into
treatment of relapsed high grade glioma were constructed. Past trials centered upon
active cell based immunization trying to present the patients' immune system with
specific antigens derived from their tumor while using different techniques to enhance
immune response. These studies has shown positive results but the need to prepare
patient specific vaccination limited their use to highly specialized centers and
results were hard to reproduce.(3)
4. The role of PD-1 in cancer immunotherapy One of the mechanisms through which tumor
cells escape immune detection is activation of the inhibitory lymphocyte receptor PD-1
(programmed death 1). Low grade activation of the T cell receptor-secondary to
prolonged antigen exposure (as found in chronic disease or protracted exposure to
malignant cells) - strongly activates- PD-1. Upon activation, PD-1 drives the
lymphocyte towards apoptosis and reduces cytokine production. PD-1/PD-1 ligand
interaction promotes tolerance of the immune system to a specific antigen (4). Lately,
studies reported high levels of PD-1 expression in tumor infiltrating lymphocytes ,and
strong expression of PD-ligand within multiple tumor types including high grade glioma
.Both these findings support the data regarding the role of PD1 in cancer immune escape
(5).
5. Anti PD-1:Safety and efficacy in human studies Over the last two years data has been
accumulating regarding efficacy and toxicity profile of anti PD-1.Topalian et.al
reported at 2012 outcome of a large phase I study evaluating antiPD-1 in advanced
cancers. Out of 296 participating patients 14% had Grade 3 or 4 drug-related adverse
events with most being treated on an outpatient setup . Several patients were diagnosed
with pneumonitis. Most were observed or treated successfully with steroids but three
patients died. Among 236 patients in whom response could be evaluated, objective
responses (complete or partial responses) were observed in those with non-small-cell
lung cancer-a cancer not known to be immunoresponsive (18%), melanoma (28% ), or
renal-cell cancer (27%). Responses were durable; 20 of 31 responses lasted 1 year or
more (6). Further studies report a better toxicity profile with similar efficacy. Hamid
et.al reported outcome of 135 patients with advanced melanoma. Side effects were mostly
grade 1-2 with no treatment related mortality. Response rate among these patients was
38% and most responses lasted at least 7 months (7). A study evaluating anti PD-1 in
chronic HCV patient revealed similar safe profile. One patient out of 66 (10 mg/kg)
experienced an asymptomatic grade 4 ALT elevation coincident with the onset of a 4-log
viral load reduction. Six patients exhibited immune-related adverse events of
mild-to-moderate intensity, including two cases of hyperthyroidism consistent with
autoimmune thyroiditis (8).
6. Anti CTLA-4 and anti PD-1 activity in brain tumors Unlike chemotherapy or targeted
therapies, both antiCTLA-4 and anti PD-1 affect T lymphocytes rather than the tumor
itself. Binding to the lymphocyte receptor may take place outside of the central
nervous system. Following binding to their receptor the reactivated lymphocytes
penetrate the brain and arrive to the tumor thus the antibodies are not required to
cross the blood brain barrier. Data regarding activity of antiCTLA-4 within the brain
may be retrieved from retrospective summary of melanoma patients with brain metastasis.
These patients are usually ineligible for clinical trials due to their grim prognosis.
Margolin e al reported partial response in 5 patients and stable disease for 12 weeks
in another 4 out of 51 patients with asymptomatic brain melanoma metastasis. Patients
with symptomatic lesions requiring steroid therapy did not respond. Di Giacomo reported
disease stabilization in 5 and near total response in another 5 patients out of 20
patients with asymptomatic metastatic melanoma lesions. These data provide proof of
principle to the assumption that this regimen is active within the brain.
Zeng et al reported improved survival of glioblastoma implanted mice following
radiation and anti PD-1. Median survival was 25 days in the control arm, 27 days in the
anti-PD-1 antibody arm, 28 days in the radiation arm, and 53 days in the radiation plus
anti-PD-1 therapy arm, these data along with tolerability of treatment calls for a
clinical trial assessing this treatment in this population with extremely poor
prognosis (9).
7. MDV9300 mechanism of action and early efficacy data
MDV9300 is one of several humanized anti PD1 antibodies currently under investigation in
multiple tumors. A single dose of MDV9300 given to mice with metastatic melanoma,
fibrosarcoma, lung carcinoma or colorectal adenocarcinoma led to significant reduction in
lung and/or liver metastases along with prolonged survival. Combination of MDV9300 with
rituximab, chemotherapy and different types of vaccines has proven to be synergistic.
In a phase I study enrolling 17 patients with advanced stage hematological malignancies
(AML,CLL, Non-Hodgkin lymphoma, Hodgkin's disease and multiple myeloma) 5 patients had
prolonged stable disease (averaging 60 weeks) and one patient with follicular lymphoma had a
complete response.
A Phase II study was conducted in 72 adult patients with DLBCL following autologous stem
cell transplantation; in this study, MDV9300 was given at a dose of 1.5 mg/kg per patient at
3 cycles per patient every 42 days (treatment Days 1, 43, and 85). The PFS and OS 18 months
after transplant were 72% and 85%, respectively. These values compare favorably with results
obtained in previous similar cohorts. In addition, the ORR within the 40 patients who
enrolled in the study with measurable disease was 45% (30%CR, 15%PR).
A Phase II study was conducted in 30 adult patients with rituximab-sensitive, grade 1-2
follicular lymphoma who relapsed after 1-4 prior therapies with measurable disease. MDV9300
was administered at 3 mg/kg IV every 4 weeks for 12 infusions and rituximab was dosed at 375
mg/m2 IV weekly for 4 weeks starting 2 weeks after the first infusion of MDV9300. Of the 29
patients eligible for efficacy analysis, 19 had an objective response for an ORR of 66%. CR
was observed in 15 (52%) and PR in 4 (14%). Altogether, 25 (86%) patients had measurable
tumor regression. The ORR of 66% and CR rate of 52% compare favorably with the previously
reported ORR of 40% and CR rate of 11% with single agent rituximab retreatment in relapsed
follicular lymphoma. Median time to response was 88 days. Of note, 17% of the patients
achieved initial response >3 months from first treatment. Median PFS was 19.6 months, and
was not reached for the 19 responders or the 25 patients with measurable tumor regression.
H. in the first part of this study eight patients were enrolled . A total of 73 cycles of
MDV9300 (range 2- 16) were applied. Treatment was well tolerated, with a mild to moderate
fatigue experienced by 10% of the patients following treatment (7 cycles). Nine cycles were
followed by neutropenia (CTCEA grade 1-3). No patient was diagnosed with neutropenia of less
than 500 cells /mm3. The only other grade 3 adverse event was a single event of transient
blood pressure during MDV9300 infusion. Median overall survival was 13 months (6-19 months)
with 50% survival at 1 year.
CONCLUSION: Anti PD1 treatment is a well-tolerated therapy with possible activity in DIPG.
