Primary objective: to determine 1) the safety, tolerability and feasibility of a single-session of HIFU-HT treatment with ICI (IV anti-PD-1; nivolumab + anti-CTLA-4; ipilimumab).Secondary objective: to evaluate clinical, radiological 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
Safety 1. Incidence and severity of adverse events (related to HIFU-HT or the
combination of HIFU-HT and ICI.) Adverse events will be assessed up to three
months after the last ICI administration.
Tolerability
1. PROMS questionnaires:
• Customized HIFU-HT-tolerability questionnaire.
• EuroQol Group EQ-5D.
• Utrecht symptom diary immunotherapy (USD-I).
2. Discontinuation rate due to adverse events.
Feasibility
1. The number of technically effective HIFU-HT procedures.
2. The percentage screening failures.
3. Time burden of the study procedures.
Secondary outcome
Radiological response
1. Local response of HIFU-HT treated tumor with a MRI directly and 12 weeks
after HIFU-HT
2. Systemic response using RECIST 1.1 as assessed by CT-scan every 12 weeks (or
using PERCIST as assessed by PET-CT if not RECIST measurable)
Immunologic response
1. Analysis of immunological parameters in peripheral blood samples (plasma and
peripheral blood mononuclear cells (PBMCs)
2. Analysis of immune infiltrates in tumor biopsies taken at baseline and 7
days after HIFU-HT
Clinical response
1. Explorative analysis to assess progression-free survival and overall
survival while taking into consideration the heterogeneous patient population
in this basket design.
Background summary
Immune Checkpoint Inhibition (ICI) has led to remarkable advances in cancer
therapy, leading to improved clinical outcomes (1,2). Cytotoxic
T-lymphocyte-associated antigen 4 (anti-CTLA-4) antibody and programmed cell
death-1 antibody (anti-PD-1) are the two most frequently used types of ICI.
Their combination has also frequently been investigated (3,4) and is part of
standard clinical practice for an increasing number of cancer types. In several
tumor types, combining CTLA4- and PD1- inhibition has been proven to improve
response rates as compared to PD1-inhibition alone (5-7) However until now, ICI
only benefits a small percentage of patients with cancer, and can be associated
with severe adverse effects (8). Despite leading to very durable responses and
at times even cure for patients with metastatic immunogenic (*hot*) tumors,
response rates for *cold* tumors to ICI have been disappointing. Many cancer
types exert this **cold** biological environment, meaning that they are either
non-immunogenic, or poorly immunogenic, and in these cases, ICI has shown
limited success.
High-intensity focused ultrasound histotripsy (HIFU-HT) is a high-intensity
focused ultrasound method that can be used to mechanically fractionate tissue.
As opposed to thermal ablation using HIFU, which involves sonication at the
same location over an extended period of time resulting in the generation of
heat, histotripsy is a mainly mechanical technique using short high-power
ultrasound pulses. The rapid oscillation between high amplitude negative and
positive peak pressures, leads to the formation and collapsing of microbubbles,
thus creating mechanical forces that lead to tissue damage and destruction (9).
In addition to its ablative use, there is growing evidence that the
immunological effects of histotripsy can enhance the efficacy of immune
checkpoint inhibitors.
In preclinical studies, it was shown that HIFU-HT can lead to the release of
tumor-associated antigens and damage-associated molecular patterns (DAMPs) for
activation of dendritic cells in the sentinel node(s), causing a sudden sterile
local inflammation (10). In preclinical murine studies, a reduction in tumor
growth was observed after treatment with histotripsy. However, in many of these
mice, tumor growth reduction was a temporal effect and mice developed
progressive disease after a period of time (11-14). Although HIFU-HT alone
triggered immunological effects in these studies, this appeared insufficient to
sustain a long-lasting systemic response.
In collaboration with the Children's National Medical Center in Washington our
research group has studied the combination of HIFU-HT with ICI (α-CTLA4 and α-
PD-1) and found a significantly improved effect of ICI in a previous
immunotherapy-refractory neuroblastoma murine model. In this study, combination
treatment resulted in improved overall response, long-lasting survival for the
majority of the mice (61%) and a memory effect that prohibited new tumors to
grow after re-inoculation with tumor cells (15). Combination of histotripsy and
ICI resulted in significant improved survival compared to mice that were
treated with histotripsy alone. These findings corroborate with other
preclinical studies that found an improved effect of immune checkpoint
inhibitors after HIFU-HT treatment (11,16,17). Histotripsy may thus have the
potential to convert a *cold* non-immunogenic tumor into a *hot* immune
responsive tumor.
An increasing number of clinical studies have been initiated in recent years
exploring the use of histotripsy in human patients. These early studies have
focused primarily on the ablative effect of histotripsy, although there is
rising attention for the potential immunological effects of histotripsy.
Histotripsy has been studied as an application in patients with benign
prostatic hyperplasia (BPH) and patients with liver tumors in multicenter
trials in both Europe and the United States (18-20). To date, the combination
of HIFU-HT and ICI has not been investigated in human patients.
The iFOCUS study is therefore the first clinical study that will assess the
safety and tolerability of HIFU-HT combined with anti-CTLA4 and anti-PD-1 in
patients. In this study, patients with advanced cancer that have progressed on
regular treatment will be treated.
Study objective
Primary objective: to determine 1) the safety, tolerability and feasibility of
a single-session of HIFU-HT treatment with ICI (IV anti-PD-1; nivolumab +
anti-CTLA-4; ipilimumab).
Secondary objective: to evaluate clinical, radiological and immunological
responses of a single-session of HIFU-HT during treatment with ICI (IV
anti-PD-1 + anti-CTLA-4).
Study design
Single-arm phase 1 clinical trial consisting of two phases:
• Phase 1 cohort 1: Six patients will be treated with the combination of
HIFU-HT and ICI.
• A safety stop is planned between phase 1 cohort 1 and phase 1 cohort 2. If no
additional safety concerns arise in this safety stop and if the funding for
phase 1 cohort 2 is guarantueed, the study proceeds to phase 1 cohort 2. The
preliminary results of phase 1 cohort 1, toghether with the documents
containing agreements concerning additional funding, will be submitted as a
substantial amendment for review by the MERC NedMec; phase 1 cohort 2 will only
be started after approval by the MERC.
• Phase 1 cohort 2: Eighteen patients will be treated with the combination of
HIFU-HT and ICI.
Intervention
The study treatment consists of intravenous administration 4 cycles qw3 of the
combination of nivolumab and ipilumumab, followed by nivolumab qw4. This first
administration of the medication occurs 1 week before HIFU-HT treatment. On day
8, patients undergo single-session HIFU-HT treatment. Additional study
procedures will include (DCE) MRI immediately after HIFU and after 12 weeks,
and follow-up visits with blood sampling and PROMS. Tumor biopsy will be taken
from the treated lesion 7 days after HIFU-HT treatment. Every three months,
response will be evaluated with CT of thorax and abdomen. Adverse events will
be followed up to 3 months after the last ICI administration.
Study burden and risks
Possible benefits of study treatment include an increased chance of tumor
response, even possibly eradicating the treated tumor, as well as other
metastases. Since the patients in the study population have progressed on
regular treatment, the risks associated with study participation are considered
proportional to the possible benefit.
Risks associated with HIFU-HT: Although HIFU has been extensively and
successfully used in patients for thermal ablation of whole tumors, the total
number of patients treated with HIFU-HT for mechanical tissue destruction is
limited yet increasing. No serious adverse events apart from one case of
urinary retention were reported from the trials to date (18-20). Risks of
HIFU-HT treatment in our trial are mitigated by real-time image-guided feedback
with thermometry. As the aim of the HIFU-HT treatment is not complete ablation
of the tumor but rather partial ablation, adjacent critical structures can be
more easily avoided in treatment planning.
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
Inclusion criteria
1. Histologically confirmed metastatic or unresectable cancer that progressed
under regular treatment options
2. Age >= 18 years.
3. Has signed and dated written informed consent before performing any study
procedure, including screening.
4. Anticipated life expectancy >= 12 weeks by Investigator judgement.
5. At least one tumor lesion (primary tumor or metastasis) which is amenable to
application of high intensity focused ultrasound histotripsy (determined by a
radiologist with HIFU-expertise).
• The lesion must have a distance of <=30 mm to the skin.
• At least part of the lesion must have a distance of >=10 mm to the skin and
other vulnerable structures (e.g. large blood vessels). This part should be
sufficient to be able to select at least one HT focus in an area of solid
tumor.
• If the target lesion contains cystic or necrotic regions: the solid component
should be >=10 mm in diameter, sufficient to be able to select at least one
HIFU-HT focus in an area of solid tumor.
6. Sonication will be performed on tumors that have not previously directly
been treated with radiation therapy or surgery unless they showed significant
mass regrowth.
7. Measurable disease (at least one lesion besides the HIFU-HT treated lesion)
on CT according to RECIST V 1.1 criteria or on PET-CT according to PERCIST
criteria as assessed by investigator and local radiology review.
8. Performance status of 0 or 1 on the WHO Performance Scale.
9. Screening laboratory values must meet the following criteria:
• WBC >= 2.0x109/L,
• Neutrophils >=1.5x109/L
• Platelets >=100 x109/L
• Hemoglobin >=5.5 mmol/L
• Serum creatinine <=1.5 x upper limit of normal (ULN) or calculated creatinine
clearance >=60 mL/minute (<=Grade 1)
• Aspartate aminotransferase (AST) <=2.5 x ULN; alanine aminotransferase (ALT)
<=2.5 x ULN; AST/ALT <5 x ULN if liver involvement
• Serum bilirubin <=1.5 x ULN or direct bilirubin <=ULN for subjects with total
bilirubin levels >1.5xULN, except in subjects with Gilbert*s Syndrome
10. Patients must agree to use an adequate method of contraception for the
course of the study through 120 days after the last dose of study medication.
11. Patients must be willing to undergo tumor biopsy.
Exclusion criteria
1. Presence of known central nervous system, meningeal, or epidural metastatic
disease. However, subjects with known brain metastases are allowed if the brain
metastases are stable for >=4 weeks before the first dose of study treatment.
Stable is defined as neurological symptoms not present or resolved to baseline,
no radiologic evidence of progression, and steroid requirement of prednisone
<=10 mg/day or equivalent.
2. Patients currently participating and receiving study therapy or patients who
participated in a study of an investigational agent and received study therapy
or used an investigational device within 4 weeks prior to the first dose of the
study treatment.
3. Prior chemotherapy, targeted small molecule therapy or monoclonal antibodies
within 4 weeks prior to the first dose of the study treatment.
4. Prior radiotherapy within 8 weeks prior to the first dose of the study
treatment. The patient will be excluded from the study if the only targetable
lesion has directly been treated with radiation therapy in the past with an
exception for lesions that showed massive regrowth.
5. Prior surgery or ablative therapy within 4 weeks prior to the first dose of
the study treatment. The patient will be excluded from the study if the only
targetable lesion has directly been treated with ablative therapy in the past.
6. Ongoing adverse events > Grade 1 due to a previously administered therapy.
Subjects with <= Grade 2 neuropathy, vitiligo, thyroid disorders,
hypocortisolism or alopecia of any grade are an exception to this criterion and
may qualify for the study.
7. History of other malignancies, except adequately treated and a
cancer-related life-expectancy of more than 5 years.
8. Concurrent medical condition requiring the use of immunosuppressive
medications, or immunosuppressive doses of systemic or absorbable topical
corticosteroids; exceeding prednisolone 10 mg or equivalent.
9. Active autoimmune disease that has required systemic treatment in the past 2
years (i.e. with use of disease modifying agents, high-dose corticosteroids or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment.
10. Active infection requiring systemic therapy.
11. History of (non-infectious) pneumonitis that required steroids or current
pneumonitis.
12. Known history of active Tuberculosis.
13. Receipt of a live vaccine within 4 weeks prior to the first dose of the
study treatment.
14. Hypersensitivity to any of the study drugs or their excipients.
15. Contra-indications to MR imaging (e.g. certain pacemakers).
Contra-indications to gadolinium-based contrast agents are not an exclusion
criterion, as a different brand of gadolinium can be used or if necessary the
MRI can be performed without contrast.
16. Pregnancy or lactation.
17. Any other medical or social condition that, in the opinion of the Principal
Investigator, might put the subject at risk of harm during the study or might
adversely affect the interpretation of the study data.
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 |
|---|---|
| CCMO | NL85300.041.23 |