Clinical trial NCT04518501: Fuzuloparib Arsenic Trioxide Platinum Resistance Relapsed Ovarian Cancer
Official title: Fuzuloparib Plus Arsenic Trioxide in Patients With Platinum Resistance Relapsed Ovarian Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Efficacy and Safety
Keywords: PARPI
Arsenic Trioxide
High Grade Serous Carcinoma
High Grade Endometria Carcinoma
Platinum-resistant Ovarian Cancer
Fuzuloparib
Lead sponsor: Women's Hospital School Of Medicine Zhejiang University
Sponsor class: OTHER
First posted: 2020-08-19
Enrollment: 50
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: Ovarian cancer is the leading cause of death from gynecologic tumors in the western world. Most patients have relapses, and responses to subsequent therapies are generally short-lived. Currently, the population that can benefit from PARPi is mainly focusing on BRCAm, then homologous-recombination deficiency patients. Limited data revealed the ORR was only 3-4% in homologous recombination proficiency patients with PARPi therapy. New treatments are urgently needed to improve patient outcomes.

To explore the efficacy and safety of Fuzuloparib in combination with Arsenic trioxide therapy in platinum-resistance relapsed Ovarian cancer patients.

Detailed description: Ovarian cancer is the leading cause of death from gynecologic tumors in the western world. Most patients have relapses, and responses to subsequent therapies are generally short-lived. Currently, the population that can benefit from PARPi is mainly focusing on BRCAm, then homologous-recombination deficiency patients. Limited data revealed the ORR was only 3-4% in homologous recombination proficiency patients with PARPi therapy. New treatments are urgently needed to improve patient outcomes.

The investigators' studies have shown that combination therapy with Fuzuloparib and Arsenic trioxide demonstrated a synergistic anti-tumor effect in BRCAness/HR-proficiency ovarian cancer cells:

Firstly, CCK8 and clone formation assays showed that the combination of Fuzuloparib and Arsenic trioxide produced notable tumor cell growth inhibition than either single agent in SKOV3 and CAOV3 cells.

Further, the combination therapy resulted in significantly increased level of γ-H2AX and decreased level of RAD51 by IF.The investigators also found that combination therapy could remarkably induced cell apoptosis, which is associated with induction of cleave-PARP and reduction of p-AKT, when compared with either single drug. (Data not published) Therefore, the investigators hypothesis is that for those platinum-resistance relapsed patients who have received at least twice platinum-based chemotherapy, patients with combinate therapy will get 25% of ORR. And platinum-resistance in combination with Arsenic trioxide therapy is well tolerated.

Eligibility criteria: Inclusion Criteria:

* 18-70years old;
* High grade (serous or endometrioid) epithelial ovarian cancers, fallopian tube or primary peritoneal carcinoma;
* Patients received at least two lines of platinum-containing chemotherapy, with recurrence occurring within six months after the last chemotherapy dose, or were platinum-refractory patients who have undergone at least two cycles of platinum-based chemotherapy;
* Measurable disease as per RECIST 1.1
* ECOG 0-2;
* Life expectancy ≥12 weeks;
* Confirmation of BRCA1/2 mutation status;
* PARPi naive;
* LVEF ≥ 50%;
* Bone Marrow Function: ANC：≥1.5×109/L； PLT：≥100×109/L；Hb: ≥90g/L;
* Liver and renal function:Serum creatinine ≤ normal upper limit (ULN) 1.5times; aspartate aminotransferase (AST) and alanine aminotransferase (ALT)≤ULN 2.5times, or \<ULN 5times in the presence of liver metastasis; total bilirubin (TBil) level≤ ULN 1.5 times, or ≤ ULN 2.5times if Gilbert's syndrome are present;
* The childbearing age subjects must agree to take effective contraceptive measures during the trial; the serum or urine pregnancy test must be negative, non-lactating;
* Signed the informed consent;

Exclusion Criteria:

* Prior treatment with PARP inhibitors except under specific conditions: 1. Patients who previously received PARP inhibitor (PARPi) therapy without disease progression during treatment, but discontinued due to reasons such as treatment cost or adherence issues; 2. Patients who received only one prior PARPi therapy (excluding fuzuloparib), with maintenance therapy lasting ≥ 12 months. In both cases, the time since the last PARPi treatment must be \>6 months prior to study enrollment;
* Patients who had previously received \>20% bone marrow radiotherapy in 1 week;
* Other malignant tumors have been found in the past 5 years,except for cured cervical carcinoma in situ, non melanoma of the skin;
* Uncontrolled systemic infection requiring anti-infective treatment;
* Allergies to the Fuzuloparib or Arsenic Trioxide or their excipients or intolerant patients;
* Subjects with ≥2 grade peripheral neuropathy according to CTCAE V 4.03;
* Researchers think it is not suitable for enrolling.

Primary outcomes:
measure: ORR
timeFrame: From date of randomization until PD or death from any cause, assessed up to 36 months.
Secondary outcomes:
measure: OS
timeFrame: From date of randomization until the date of death from any cause, or date of last follow-up for patients still alive, assessed up to 36 months]
measure: PFS
timeFrame: From date of randomization until the date of first documented progression or death from any cause, whichever occurred first, or last follow-up for patients alive without progression, assessed up to approximately 36 months
measure: the incidence and severity of adverse reactions
timeFrame: A summary of adverse events of each cycle,from date of administration of drugs until 30 days after the last chemotherapy or progression,whichever came first,assessed up to 36 months
measure: quality of life assessment
timeFrame: It will be assessed at baseline and before the administration of drugs at each first day of every two chemotherapy cycles, up to 6 cycles,each cycle is 28days.
Other outcomes:
Locations:
city: Zhejiang
country: China
facility: Women's Hospital School Of Medicine Zhejiang University
state: Hangzhou
Study officials:
References: