Phase1: To characterize the safety and tolerability of isatuximab in combination with atezolizumab in participants with unresectable hepatocellular carcinoma (HCC), platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase 1:
- Dose limiting toxicities (DLTs) (in Cycle 1)
- Adverse events (AEs)/serious adverse events (SAEs),
- Laboratory abnormalities and the recommended Phase 2 dose (RP2D) defined as
the dose selected for the Phase 2 portion.
Phase 2 :
- RR defined as the proportion of patients with complete response and partial
response as best overall response (assessed by Investigators using RECIST
criteria 1.1 for patients with HCC, SCCHN and EOC;
- PFS-6 defined as the PFS rate at 6 months assessed by Investigators using
RANO criteria for GBM.
Secondary outcome
Phase 2:
- Adverse events (AE)/serious AEs and laboratory abnormalities;
- Incidence rate of anti-drug antibodies development (ADA: anti-isatuximab and
anti-atezolizumab antibodies)
- PK assessed from concentrations of isatuximab (non-compartmental analysis and
population PK approach) and atezolizumab (population PK approach).
- Best percent-change from baseline in tumor burden change, disease control
rate (DCR) defined as the sum of the complete response, partial response and
stable disease rates, duration of response (DoR), progression free survival
(PFS) (HCC, SCCHN, EOC per RECIST 1.1 and GBM per RANO criteria), RR (GBM only,
per RANO criteria).
Background summary
Monoclonal antibodies that block the PD-1/PD-L1 axis have changed the landscape
of cancer therapy. Despite the success of PD-1/PD-L1 blockers, optimal outcomes
for many patients will require combination therapies. In solid tumors, CD38 is
found expressed on the tumor cells of treatment naïve prostate adenocarcinoma
and glioblastoma biopsies. A recent report has shown that the combination of
anti-PD-L1 and CD38 antibodies induces a greater anti-tumor immune response
than anti-PD-L1 in a mouse lung cancer model.
Isatuximab can induce different immuno-modulatory mechanisms that can
contribute to reshape the tumor microenvironment and enhance the anti-tumor
activity of anti-PD-1 antibodies. Isatuximab has shown clinical response in
relapsed/refractory MM patients as a single agent and in combination with
immunomodulatory agents. Although isatuximab has not been tested yet in solid
tumors, we hypothesize, based on the immunomodulatory activities described
above, that isatuximab may contribute to reshaping the tumor immune-environment
and will enhance the activity of anti-PD-L1 therapy.
The current study (ACT15377) will evaluate the safety, tolerability, and RRs of
isatuximab in combination with atezolizumab as primary objective in patients
with solid tumors; unresectable HCC, recurrent/metastatic SCCHN,
platinum-resistant/refractory recurrent EOC and recurrent GBM. In HCC, SSCHN,
EOC the presence of PD-1 expressing lymphocytes support the use of PD-1/PD-L1
immune checkpoint blockade as a therapeutic strategy. In GBM the PD-1/PD-L1
pathway is recognized as a therapeutic strategy, CD38 expression is observed in
GBM which suggest the addition of a anti CD38 therapy to anti PD-1/PD-L1 may
potentiate tumor-specific immune reponse.
Study objective
Phase1: To characterize the safety and tolerability of isatuximab in
combination with atezolizumab in participants with unresectable hepatocellular
carcinoma (HCC), platinum-refractory recurrent/metastatic squamous cell
carcinoma of the head and neck (SCCHN), platinumresistant/refractory epithelial
ovarian cancer (EOC), or recurrent glioblastoma multiforme (GBM), and to
determine the recommended Phase 2 dose (RP2D).
Phase2:
- To assess response rate (RR) of isatuximab in combination with atezolizumab
in participants with HCC or SCCHN or EOC.
- To assess the progression free survival rate at 6 months (PFS-6) of
isatuximab in combination with atezolizumab, or as a single agent in
participants with GBM.
Study design
This is a Phase 1/2 open-label, non-randomized, multi-center, safety,
preliminary efficacy, and PK study of isatuximab in combination with
atezolizumab, or isatuximab alone in participants with advanced malignancies.
The study will be conducted in 2 phases.
Phase 1 is the safety run-in for the determination of the maximum tolerated
dose and RP2D for the isatuximab and atezolizumab combination.
Phase 2 investigates the efficacy of the RP2D isatuximab and atezolizumab
combination with a 2-stage design. Enrollment in Cohort A, B, C and D-1 will be
performed in parallel. Then enrollment in Cohort D-2 and E will be performed
sequentially at the end of each respective Stage 2 of previous cohorts
depending on results observed.
Intervention
Phase 1: patients receive 1200 mg once every 3 weeks (Q3W) for atezolizumab
with isatuximab given 10 mg/kg or 5 mg/kg once weekly for 3 weeks followed by
Q3W.
Phase 2: patients receive 1200 mg once every 3 weeks for atezolizumab with
isatuximab given dose based on results from phase 1 once weekly for 3 weeks
followed by Q3W.
Study burden and risks
The risks are related to the blood samples and the possible side effects of the
study medication.
The burden on the patient will be the frequency of visits to the research
center.
Kampenringweg 45 E
Gouda 2803 PE
NL
Kampenringweg 45 E
Gouda 2803 PE
NL
Listed location countries
Age
Inclusion criteria
- Patients must have a known diagnosis of either unresectable hepatocellular carcinoma (HCC), platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN), platinum-resistant/refractory epithelial ovarian cancer (EOC) with evidence of measurable disease;or recurrent glioblastoma multiforme (GBM).;- *18 years of age.;-For patients with HCC: Documentation of progressive disease (PD) during or after treatment with either sorafenib or lenvatinib, or intolerance to the therapy.;-For patients with SCCHN: Received and failed up to 2 lines of prior systemic anti-cancer therapy with documentation of tumor recurrence or PD within 6 months of last platinum-based therapy in primary, recurrent, or metastatic setting.;-For patients with EOC: Received and failed up to 3 lines of prior platinum-containing therapy when the disease was platinum-sensitive, and the patients should not have received any systemic therapy for platinum-resistant/refractory disease.;-For patients with GBM: Documentation of PD or first recurrence during or after temozolomide maintenance therapy for newly diagnosed GBM treated with 1st line radiotherapy plus concurrent temozolomide.
Exclusion criteria
- Prior exposure to agent that blocks CD38 or participation in clinical studies with isatuximab;- For patients with HCC, SCCHN, EOC or GBM prior exposure to any agent (approved or investigational) that blocks the PD-1/PD-L1 pathway.;- Evidence of other immune related disease /conditions.;- History of non-infectious pneumonitis requiring steroids or current pneumonitis; history of the thoracic radiation.;- Has received a live-virus vaccination within 28 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.;- Prior solid organ or bone marrow transplantation.;- Eastern Cooperative Oncology Group performance status (PS) *2 for patients with HCC, SCCHN or EOC or Karnofsky performance score * 70 for patients with GBM;- Poor bone marrow reserve.;- Poor organ function.
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 | EUCTR2018-000390-67-NL |
| CCMO | NL65453.078.18 |
| Other | U1111-1202-0839 |