Single-arm Phase II Clinical Trial to Evaluate the Initial Efficacy and Safety of Sintilimab Injection Combined With Inlyta in Fumarate Hydratase- Deficient Renal Cell Carcinoma
Phase: PHASE2
Conditions: Carcinoma, Renal Cell, Fumarate Hydratase Deficiency, Immunotherapy
Sponsor: West China Hospital

Single-arm phase II clinical trial to evaluate the initial efficacy and
safety of Sintilimab injection combined with Inlyta in fumarate
hydratase-deficient renal cell carcinoma
FH- fumarate hydratase
RCC- renal cell carcinoma
primary investigator: Hao Zeng
Contacts/Locations
Central Contact Person: Hao Zeng, Doctor
Telephone: 8618980602129
Email: kucaizeng@163.com
2019-8-15
Study Background
Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a kind of
autosomal dominant diseases featured by FH gene mutation [1]. Since
FH-deficient RCC not only demonstrates distinct genetic alteration patterns
and also shows a very aggressive clinical pattern, WHO/ISUP has redefined it
as
a RCC subtype (it was once classified into papillary RCC (pRCC)) [2].
FH-deficient RCC patients are likely to develop metastasis at the early phase,
and they also response poorly to common targeted drugs in RCC. In another
words, there is no standard therapy for FH-deficient RCC.
Loss-of-function mutation of FH results in accumulation of fumarate,
impairment of oxidative phosphorylation, alteration of metabolic state, and
stabilization of hypoxia-inducible factor (HIF)-1α, ultimately leading to the
activation of angiogenic and oxidative stress response pathways [3-5].
Evidence suggests that accumulated fumarate also diminishes AMPK levels
and consequent activation of mTOR and downstream pathway. Although there
are current results of clinical trials (NCT01130519 and NCT01399918)
suggesting the use of bevacizumab plus erlotinib or everolimus as standard

treatment for FH-deficient RCC [6, 7]. However, we retrospectively analyzed
eight confirmed FH-deficient RCC in our center between 2010-2018 and found
that most (7/8，87.5%) of them did not respond well to targeted therapy (TKIs
and/or mTOR inhibitors.
To date, effective treatments for FH-deficient RCC remain a major unmet
clinical need. Unlike three other subtypes of RCC, including clear cell RCC
(ccRCC), pRCC and chromophobe RCC (chRCC), the genomic landscape of
HLRCC has not yet been reported. Without any genomic information, it is
challenging to develop targeted therapy and clinical trials for FH-deficient RCC.
We previously performed a Whole-exosome sequencing on FH-deficient RCC
cases confirmed at our center and found that it harbored high rate of
microsatellite instability (MSI), high PD-L1 positive rate. Consequently, we
concluded that these patients might be sensitive to immunotherapy.
Currently numerous studies have shown that immunotherapy might be an
important tool in RCC treatment [8-10], while first-line PD-1/PD-L1 inhibitors
showed
an
merely
20%-30%
overall
response
rate
and
a
similar
progression-free survival to that of targeted therapy. Considering the possible
crosstalk
between
antiangiogenic
therapy
and
tumor
immune
microenvironment, the immunogenicity of FH-deficient RCC could hinder the
efficacy
of
TKI
monotherapy,
which
indicates
that
combination
of
immunotherapy and TKI might be a potential way. Therefore, we intend to
perform this clinical trial.
Reference:
1.
Tomlinson, I.P., et al., Germline mutations in FH predispose to
dominantly inherited uterine fibroids, skin leiomyomata and papillary
renal cell cancer. Nat Genet, 2002. 30(4): p. 406-10.
2.
!!! INVALID CITATION !!! [2].
3.
Isaacs, J.S., et al., HIF overexpression correlates with biallelic loss of
fumarate hydratase in renal cancer: novel role of fumarate in regulation
of HIF stability. Cancer Cell, 2005. 8(2): p. 143-53.
4.
Mullen, A.R., et al., Reductive carboxylation supports growth in tumour

cells with defective mitochondria. Nature, 2011. 481(7381): p. 385-8.
5.
Ooi, A., et al., An antioxidant response phenotype shared between
hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer
Cell, 2011. 20(4): p. 511-23.
6.
Srinivasan, R., et al., 5 Mechanism based targeted therapy for
hereditary leiomyomatosis and renal cell cancer (HLRCC) and sporadic
papillary renal cell carcinoma: interim results from a phase 2 study of
bevacizumab and erlotinib. European Journal of Cancer, 2014. 50.
7.
Voss, M.H., et al., Phase II Trial and Correlative Genomic Analysis of
Everolimus Plus Bevacizumab in Advanced Non-Clear Cell Renal Cell
Carcinoma. J Clin Oncol, 2016. 34(32): p. 3846-3853.
8.
Kusmartsev, S., et al., Oxidative Stress Regulates Expression of
VEGFR1 in Myeloid Cells: Link to Tumor-Induced Immune Suppression
in Renal Cell Carcinoma. The Journal of Immunology, 2008. 181(1): p.
346-353.
9.
Wallin, J.J., et al., Atezolizumab in combination with bevacizumab
enhances antigen-specific T-cell migration in metastatic renal cell
carcinoma. Nat Commun, 2016. 7: p. 12624.
10.
Najjar,
Y.G.,
et
al.,
Myeloid-Derived
Suppressor
Cell
Subset
Accumulation in Renal Cell Carcinoma Parenchyma Is Associated with
Intratumoral Expression of IL1beta, IL8, CXCL5, and Mip-1alpha. Clin
Cancer Res, 2017. 23(9): p. 2346-2355.
Protocol
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 2
Interventional Study Model: Single Group Assignment
Number of Arms: 1
Masking: None (Open Label)
Allocation: N/A
Enrollment: 20 [Anticipated]
Experimental: Sintilimab injection combined with Inlyta (Sintilimab injection
10ml: 100mg, 200mg intravenously, once every three weeks. Course of
treatment: discontinue medication when the disease progresses clinically or
radiologically. Inlyta 5mg orally, twice a day. Course of treatment: continue
treatment as long as a clinical benefit is observed, or until an unacceptable
toxicity is present that cannot be controlled by combination or dose
adjustment.)

In the whole research process, if the disease progresses, the attending doctor
has the right to carefully choose other anti-tumor methods, including
radiotherapy, chemotherapy and other targeted drugs
Outcome Measures
Primary Outcome Measure:
1. PFS: progression-free survival
[Time Frame: 3 years]
2. ORR: objective response rate
[Time Frame: 3 years]
Secondary Outcome Measure:
3. OS: overall survival
[Time Frame: 3 years]
4. life quality: evaluate life quality
[Time Frame: 3 years]
Other Pre-specified Outcome Measures:
5. drug related adverse effect
[Time Frame: 3 years]
Eligibility
Minimum Age: 18 Years
Maximum Age:
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria: Inclusion Criteria:
1. age ≥18;
2. histology characteristics accord with FH-deficient RCC;
3. gene testing confirms germline and/or somatic FH gene mutation ;
4. ECOG (Eastern Cooperative Oncology Group)≤2;
5. expected survival >3 months;
6. blood routine indexes: neutrophils ≥1.5*109, platelets ≥100*109,
hemoglobin ≥90g/L;
7. liver function: bilirubin ≤normal upper limit 1.5 times, AST≤normal
upper limit 2.5 times;Serum creatinine ≤1.5 times of normal upper
limit;Serum calcium concentration: ≤12.0 mg/dL;
8. coagulation function: PT≤1.5 times of normal upper limit;
9. the following diseases did not appear within 12 months: myocardial
infarction, severe or unstable angina pectoris, asymptomatic heart
failure, cardiovascular and cerebrovascular accident or transient
ischemic attack, etc.
10. all patients signed informed consent.
Exclusion Criteria:
1. other malignancies previously or at the same time that are different

from the primary site or histology of the tumor assessed in this study,
except cervical carcinoma in situ, basal-cell carcinoma that has been
fully treated, superficial bladder tumor (Ta, Tis, T1) or other malignancies
that occurred before the enrollment and have been cured for more than
3 years;
2. renal decompensation requires hemodialysis or peritoneal dialysis;
3. arrhythmia need anti-arrhythmic treatment, symptomatic coronary
artery disease or myocardial ischemia (myocardial infarction), nearly six
months, or congestive heart failure than NYHA # level; Hypertension
(systolic blood pressure >160 mmHg or diastolic blood pressure >100
mmHg) that has been treated with 2 or more antihypertensive treatments
and still cannot be controlled;
4. severe active clinical infection;
5. patients with coagulation disorder or bleeding constitution;
6. major surgery or severe trauma was performed within 4 weeks before
enrollment;
7. a history of allogeneic organ transplantation or bone marrow
transplantation;
8. drug abuse and medical, psychological or social conditions that may
interfere with patients' participation in research or affect the evaluation of
results;
9. known or suspected allergy to the study drug;
10. those who received treatment other than this study within 4 weeks prior
to and during the study period.