Primary objectives: - To assess safety and feasibility of neoadjuvant nivolumab +/- domatinostat +/- ipilimumab- To identify pathologic response rates of nivolumab +/- domatinostat +/- ipilimumabSecondary objectives: - To describe all grade…
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Brief title
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- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Safety and feasibility of patients as measured by the adherence to the
timelines in the study protocol. A treatment arm will be declared as not
feasible if 2/5 or 4/10 patients cannot adhere to the planned time of surgery
(week 6 +/- 1 week) due to treatment related adverse events.
- Pathologic response rates (pPR, near-pCR, and pCR).
Secondary outcome
- Frequency of treatment-related toxicities as measured according to CTCAE 5.0.
- RFS, as determined according to RECIST 1.1 criteria.
- Identification of RNA signatures associated with pathologic response and RFS
for each arm (by RNAseq and NanoString gene expression analysis).
- Characterization of changes in immune infiltrates/markers at week 3 and/or 6
compared to baseline by NanoString DSP technology.
- Inter-arm comparison of the expansion of tumor-resident T cell clones, as
measured by TCR sequencing of the baseline tumor-biopsy and PBMC samples from
baseline week 3 and week 6.
- Feces microbiome diversity analyses and its correlation with pathologic
response and toxicities.
- Quality of life as measured by EORTC QLQ C30, the melanoma and the surgery
subscale of FACT-M, the Cancer Worry Scale, HADS questionnaire and assessment
of work performance.
Background summary
T cell checkpoint blockade by anti-CTLA and/or anti-PD1 is currently the most
promising therapy in late stage melanoma to induce long-term benefit or even
cure. Particularly the combination of ipilimumab and nivolumab induces high
response rates and promising response depth. In earlier stage melanoma
ipilimumab + nivolumab is currently tested in the adjuvant setting (Checkmate
915, NCT03068455) in stage III melanoma, after ipilimumab, nivolumab, and
pembrolizumab monotherapies have all shown to improve relapse free survival
(RFS), and overall survival (OS, to date only for ipilimumab) in phase 3
trials. In addition, adjuvant targeted therapy using the BRAF+MEK inhibitor
combination of dabrafenib + trametinib in BRAFV600E/K mutation positive
patients has been shown to improve RFS and OS (only RFS significantly).
In contrast to chemotherapeutic approaches, immunotherapeutic approaches depend
on sufficient activation of the immune system. To become fully activated, T
cells require two signals. The first signal is provided by the interaction of
the (tumor-) antigen presented in the major histocompatibility complex (MHC) on
the antigen-presenting cell (APC) to the T cell receptor (TCR) on the T cell
(signal 1). In parallel, a large number of co-inhibitory and co-stimulatory
interactions - so-called T cell checkpoints - modulate the outcome of the TCR -
MHC interaction. Antibody-based interference with the T cell checkpoints CTLA-4
and PD-1 has been shown to improve tumor-specific T cell responses and to
result in a significant clinical benefit in patients with melanoma and other
cancers.
The notion that T cell checkpoint inhibition is of greatest value at the moment
of TCR triggering has potentially significant consequences for the use of
checkpoint targeting antibodies as adjuvant therapies. Specifically, as the
amount of antigen that can provide this signal 1 will correlate with tumor
load, adjuvant immunotherapy can be assumed to work most efficiently, when
adjuvant treatment is initiated prior to surgery (neoadjuvant treatment).
In melanoma, this concept was pioneered by the Netherlands Cancer Institute
testing in a phase 1 trial neo-adjuvant and adjuvant application of 4 courses
of ipilimumab + nivolumab in stage III melanoma (OpACIN, CA209-278,
NCT02437279), showing that neo-adjuvant immunotherapy was feasible, but with
the current standard regimen (4 courses ipilimumab 3mg/kg + nivolumab 1mg/kg)
too toxic for (neo)adjuvant application. Pathologic responses (pRR) after only
6 weeks of neoadjuvant ipilimumab + nivolumab were high with 78%, and all
responders are free of relapse with a median follow-up of 32 months. The
expansion of tumor-resident T cell clones was more frequent after neoadjuvant
application and a baseline interferon (IFN)-gamma signature was associated with
outcome (IFN-gamma low patients had a very high chance for relapse after
neoadjuvant ipilimumab + nivolumab).
The observed feasibility and pathologic responses, combined with the observed
toxicity, formed the rationale for the design of the subsequent phase 2 trial,
OpACIN-neo (NCT02977052), that compared safety and efficacy of three different
dosing schemes of neo-adjuvant ipilimumab + nivolumab. With only two
neoadjuvant courses of ipilimumab + nivolumab, this trial confirmed the high
efficacy of targeting CTLA-4 and PD-1 in the neoadjuvant setting and identified
a combination scheme (ipilimumab 1mg/kg + nivolumab 3mg/kg) that was tolerated
(20% grade 3/4 toxicity rate with no specific grade 3/4 toxicity >5%), while
efficacy was preserved (77% pRR). Again, the baseline IFN-gamma signature
discriminated patients with a high chance for relapse (IFN-gamma signature low)
and no relapse (IFN-gamma signature high) after neoadjuvant ipilimumab +
nivolumab. The signature was insufficient discriminative in this larger cohort
for intermediate IFN-gamma signature patients.
The identified winner combination is currently tested in the PRADO extension
cohort to confirm the pRR and toxicity rate in a larger cohort of patients. The
other aim of the PRADO extension cohort is to test whether a subsequent lymph
node dissection can be omitted in patients achieving a major pathologic
response (pCR or near pCR).
However, as only 77-78% of patients have pathologic response upon neoadjuvant
ipilimumab + nivolumab, and patients with no pathologic response are at very
high risk for relapse (currently 57%), there is a need for identification of
new treatment combinations that can induce responses in patients that do not
respond to neoadjuvant ipilimumab + nivolumab.
Patients that do relapse after neoadjuvant ipilimumab + nivolumab are
characterized, in addition to the negative IFN-gamma signature, by low PD-L1
expression, low tumor T cell infiltration, and lower b2m expression.
Domatinostat tosilate (domatinostat) is an orally available HDACi that
specifically inhibits the class I HDAC isotypes 1, 2 and 3. In preclinical
studies, domatinostat inhibits Wnt and Hedgehog (HH) signaling pathways, which
are relevant for proliferation, differentiation and metastasis of tumor cells.
In addition, in preclinical models it has been shown that domatinostat
increases tumor T cell infiltration, MHC and CD86 expression and presentation
of tumor-associated antigens. Furthermore, the combination of domatinostat with
checkpoint inhibitors (PD-1 or PD-L1) resulted in reduced tumor growth and
prolongued survival in syngeneic mouse models. This makes domatinostat an
attractive combination partner for checkpoint inhibitors and other
immunotherapies.
Since the combination of domatinostat with anti-PD-(L)1 did not increase the
frequency or intensity of immune-related AEs, domatinostat could be a
well-tolerated combination partner for checkpoint inhibiting antibodies in
stage III disease.
These hypotheses form the rationale for DONIMI, a phase 1b trial testing the
combination of domatinostat + nivolumab or nivolumab monotherapy in IFN-gamma
signature high patients and of domatinostat + nivolumab or domatinostat +
nivolumab + ipilimumab in IFN-gamma signature low patients with de-novo or
recurrent macroscopic stage III cutaneous or unknown primary melanoma.
Study objective
Primary objectives:
- To assess safety and feasibility of neoadjuvant nivolumab +/- domatinostat
+/- ipilimumab
- To identify pathologic response rates of nivolumab +/- domatinostat +/-
ipilimumab
Secondary objectives:
- To describe all grade toxicities of the regimens
- To describe relapse free survival (RFS)
- To identify subgroups of patients benefiting from the individual schemes
- To compare the immune activating activity of the combination schemes
- To identify baseline biomarkers predictive for pathologic complete response
(pCR)/pathologic near complete response (pnCR)
- To evaluate health related quality of life
Study design
This is an open-label phase 1b trial consisting of 45 stage III cutaneous or
unknown primary melanoma patients with RECIST 1.1 measurable de-novo or
recurrent disease (short axis lymph node metastasis >=1.5cm).
NanoString IFN-gamma signature high patients will be randomized to:
- 6 weeks neo-adjuvant treatment with nivolumab (10 patients).
- 6 weeks neo-adjuvant treatment domatinostat + nivolumab (10 patients).
NanoString IFN-gamma signature low patients will be randomized to :
- 6 weeks neo-adjuvant treatment with domatinostat + nivolumab (10 patients)
- 6 weeks neo-adjuvant treatment with domatinostat + nivolumab + ipilimumab (20
patients). Based on the safety data of this dosing scheme, the domatinostat
dose can be increased (200mg BID, d1-14, q3wks), decreased (100mg OD, d1-14,
q3wks) or kept at the same dosing scheme 200mg OD, d1-14, q3wks). The trial was
initially designed to decide on the dose increase/decrease after 5 patients
were treated in arm D. However, based on the safety data of the first 5
patients in arm D, the DSMB advised to continue with the same dosing scheme of
200mg OD, d1-14, q3wks and to re-evaluate a potential dose increase after 10
patients. After 10 patients were treated, the DSMB decided that is was safe to
increase the domatinostat dose to the 200mg BID dosing scheme, d1-14 q3wks. We
therefore expanded this arm with 10 extra patients to be treated with the 200mg
BID scheme (20 patients in total) for the evaluation of feasibility and safety.
Post-surgery (starting at week 12), the patients will start with adjuvant
nivolumab or pembrolizumab for 52 weeks according to institute*s standard. In
case of no pathologic response after neoadjuvant immunotherapy, the alternative
application of adjuvant dabrafenib + trametinib should be considered in
BRAFV600E/K mutation positive patients.
Follow-up after the adjuvant therapy will be for 2 years, according to the
institutes* standard.
Screening will require approximately 80-100 patients (NanoString IFN-gamma
signature) to identify the 20 IFN-gamma signature low and 20 IFN-gamma
signature high patients.
Toxicity and pathologic response rates will be descriptive.
In case of 2/5 or 4/10 patients not undergoing their lymph node dissection at
week 6 +/- 1 week due to treatment related toxicity, this arm will be declared
unfeasible.
Intervention
In DONIMI patients will be treated pre-surgically for 6 weeks with the
combination of nivolumab +/- domatinostat +/- ipilimumab. For ipilimumab and
nivolumab flat-dose equivalents of the winner scheme identified in OpACIN-neo
will be applied.
Medicine tested: 2 courses nivolumab 240mg q3wks +/- domatinostat 200mg QD,
d1-14, q3wks +/- ipilimumab 80mg q3wks.
Lab testing (incl. collection of PBMC, plasma, serum, feces) will be performed
during screening, at week 3, and at week 6 pre-surgery.
Tumor biopsies for material preservation is required at baseline, week 3, and
from the surgery specimen.
CT scans will be required at baseline and at week 6.
Follow-up will start at week 12 with a CT or PET /CT scan according to the
individual center*s standard. Subsequent follow-up will be by PET/CT or CT
scans according to the national*s/institutional*s standards for high-risk
melanoma (3 monthly most common standard).
Collection of additional PBMC, plasma, serum, feces, and tumor biopsies will be
performed in case of relapse.
Study burden and risks
Standard adjuvant therapy for patients with high-risk stage III melanoma is
currently either nivolumab, pembrolizumab or adjuvant dabrafenib + trametinib
(for BRAF V600 mutant patients only). These standard options are based on phase
3 trials showing improved RFS without showing significant OS benefit so far.
Adjuvant nivolumab and pembrolizumab improved significantly RFS (as compare to
ipilimumab and placebo respectively). Treatment-related grade 3/4 toxicity
rates were low with 14.4% and 14.7%. The screen failure rate was high in the
adjuvant pembrolizumab E1325 trial, with a total of 30% screen failures, and
14% due to early relapse within 12 weeks post-surgery, making RFS judgement
comparing adjuvant and neoadjuvant trials (latter representing more
intention-to-treat populations) hard to compare due to the high patient
selection in the adjuvant trials.
Adjuvant dabrafenib + trametinib also improved significantly the RFS in BRAF
V600 mutation-positive patients. Grade 3/4 toxicity rate was 41% as compared to
14% in the placebo arm, and thus clearly higher than for adjuvant anti-PD-1.
The participants in this trial will be exposed to one or two immunotherapeutic
agents (ipilimumab, nivolumab) known to induce immune related adverse events,
resulting in expected higher grade 3/4 toxicities rate of at least 20% (as
based on the OpACIN-neo trial data). Therefore, the rate of grade 3/4 toxicity
is expected to be higher than for anti-PD-1 adjuvant therapies, but lower than
for the standard adjuvant BRAF + MEK inhibition. While such immune-related
adverse event could hamper on-time surgery, we have not observed this within
our OpACIN and OpACIN-neo trials.
Domatinostat is currently under evaluation in two phase 1b/2 trials in
combination with pembrolizumab and in combination with avelumab (SENSITIZE and
EMERGE). The pattern of AEs in the combination trials were mild to moderate and
similar to the one in the TOPAS monotherapy trial. No increase in frequency or
intensity of immune-related AEs could be observed in combination with
anti-PD-(L)1 antibodies so far (cut-off-date: 15-July-2019). In a third trial
(KN0142) the HDAC inhibitor entinostat was combined at standard dosing of 5mg
qw with pembrolizumab 200mg q3w (Sullivan et al., AACR 2019). Similarly, in
this trial the addition of the HACDi did not increase the frequency of grade
3/4 immune related toxicities beyond the expected percentages known for
prembrolizumab monotherapy (9.4% grade 3/4 toxicities with rash, colitis,
pneumonitis and ir hepatitis being most frequent ranging fom 1.9 to 3.8%). We
expect that the same will be the fact for the triple combination of ipilimumab,
nivolumab and domatinostat in stage III patients. However, since the triple
combination has not been tested in humans before, the first 5 patients in this
arm will be treated with a lower dose of domatinostat (200mg OD, d1-14)
followed by the 200mg BID, d1-14 dosing scheme.
Additional burden evolving from participation in this trial are extra blood
draws, two additional CT scans, feces collection, and two (three in case of
relapse) additional tumor biopsies. Also, patients are asked to fill in a diet
questionnaire and several questionnaires about their quality of life.
On the benefit side, patients treated in this trial with neoadjuvant checkpoint
inhibition and HDACi can be judged concerning their pathologic response, and if
needed, the therapy can be adjusted for the adjuvant therapy if other adjuvant
therapies are approved and available. This might lead to a benefit for the
individual patient concerning their outcome as compared to applying standard
adjuvant therapy only.
To ensure the safety of these patients, a data safety monitoring board will be
installed, and a strict safety rule will be implemented, closing any treatment
cohort if 2/5 or 3/10 patients are unable to undergo their lymph node
dissection due to treatment related adverse events from the neoadjuvant
immunotherapy combination.
For arm D, the DSMB will be consulted after 5 patients are treated with the
lower domatinostat dose (200mg OD, d1-14). Based on the amount of grade 3-4
AEs, completion of two neoadjuvant treatment cycles and timely performance of
surgery, the decision will be made about proceeding into the higher
domatinostat dosing schedule (200mg BID, d1-14).
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
- Adults at least 18 years of age.
- World Health Organization (WHO) Performance Status 0 or 1.
- Cytologically or histologically confirmed resectable stage III cutaneous
melanoma (unknown primary also allowed) with one or more macroscopic lymph node
metastases (measurable according to RECIST 1.1), that can be biopsied, and no
history of in-transit metastases within the last 6 months.
- IFN-gamma signature low or high according to the NanoString test (IFN-gamma
signature intermediate not allowed).
- No other malignancies, except adequately treated and a cancer-related
life-expectancy of more than 5 years.
- Patient willing to undergo quadruple tumor biopsies and extra blood
withdrawal during screening, week 3 and in case of relapse.
- No immunosuppressive medications within 6 months prior trial registration.
- 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, Creatinine <=1.5x ULN, AST <= 1.5 x ULN, ALT <= 1.5 x ULN, Bilirubin <=1.5
X ULN.
- Normal LDH.
- Women of childbearing potential must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours
prior to the start of ipilimumab + nivolumab.
- Patient is capable of understanding and complying with the protocol
requirements and has signed the Informed Consent document.
Exclusion criteria
- Distantly metastasized melanoma.
- Uveal or mucosal melanoma.
- History of in-transit metastases within the last 6 months.
- No measurable lymph node lesion according to RECIST 1.1.
- Subjects with any active autoimmune disease or a documented history of
autoimmune disease, or history of syndrome that required systemic steroids or
immunosuppressive medications, except for subjects with vitiligo or resolved
childhood asthma/atopy.
- Patients with any active gastrointestinal disorder that could interfere with
the absorption of domatinostat (as per judgement of the investigator), such as
ulcerative colitis, Crohn*s disease, diabetic gastroparesis, or other syndromes
characterized by malabsorption.
- Prior CTLA-4 or PD-1/PD-L1 targeting immunotherapy.
- Prior radiotherapy.
- Patients will be excluded if they test positive for hepatitis B virus surface
antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody),
indicating acute or chronic infection; if treated and being at least one year
free from HCV patients are allowed to participate.
- Patients will be excluded if they have known history of testing positive for
human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome
(AIDS).
- Allergies and Adverse Drug Reaction:
- History of allergy to study drug components;
- History of severe hypersensitivity reaction to any monoclonal antibody.
- Underlying medical conditions that, in the Investigator's opinion, will make
the administration of study drug hazardous or obscure the interpretation of
toxicity or adverse events.
- Patients with a marked baseline prolongation of QT/QTc interval, e.g.,
repeated demonstration of a QTc interval >450 msec (Grade 1 NCI-CTCAE);
Long-QT-Syndrome) and patients receiving agents known to prolong the QT
interval and known risk of Torsades de Pointes.
- Patients with significant current cardiovascular disease including:
- Unstable angina pectoris within 6 months prior to screening
- Uncontrolled hypertension
- Congestive heart failure (New York Heart Association (NYHA) Class III or
IV) related to primary cardiac disease
- Conditions requiring anti-arrhythmic therapy (patients with status post
pace maker implantation can be included)
- Symptomatic ischemic or severe valvular heart disease, or a myocardial
infarction within 6 months prior to the trial entry
- Women who are pregnant or lactating
- Use of other investigational drugs before study drug administration 30 -days
and 5 half-times before trial registration.
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 | EUCTR2019-002878-30-NL |
| ClinicalTrials.gov | NCT04133948 |
| CCMO | NL70859.031.19 |