Camrelizumab Plus Apatinib in Patients With High-risk Gestational Trophoblastic Neoplasia

Camrelizumab Plus Apatinib in Patients With High-risk Gestational Trophoblastic Neoplasia: a Cohort, Open-label, Phase 2 Trial

The purpose of this study is to evaluate the efficacy and safety of camrelizumab and apatinib as combination therapy in patients with ultra high-risk (Cohort A) and high-risk chemo-refractory or relapsed (Cohort B) gestational trophoblastic neoplasia (GTN). Eligible patients will receive camrelizumab plus apatinib plus chemotherapy. Treatment will be continued until disease progression, unacceptable toxicity, or withdrawal of consent.

Study Overview

• Status: Recruiting
• Conditions: Gestational Trophoblastic Neoplasia
• Intervention / Treatment: Drug: Camrelizumab plus apatinib CohortA; Drug: Camrelizumab plus apatinib Cohort B

Detailed Description

The purpose of this study is to evaluate the efficacy and safety of camrelizumab and apatinib as combination therapy in patients with ultra high-risk (Cohort A) and high-risk chemo-refractory or relapsed (Cohort B) gestational trophoblastic neoplasia (GTN).

Cohort A: Eligible patients will receive camrelizumab (200mg q2w iv) plus apatinib (250 mg qd po) plus chemotherapy. After normalization of serum β-human chorionic gonadotropin (β-hCG) levels, patients will receive 4 cycles of consolidation chemotherapy combined with camrelizumab plus apatinib and then 6 months of camrelizumab plus apatinib as maintenance treatment. Treatment will be continued until completion of treatment, disease progression, unacceptable toxicity, or withdrawal of consent.The primary endpoint is complete remission rate (the proportion of patients achieving complete remission). Secondary endpoints include objective response rate (the proportion of patients achieving complete remission and partial remission), progression-free survival (time from the treatment initiation to disease progression or death, whichever comes first), overall survival (time from the treatment initiation to the date of death or last follow-up), duration of response (time from the first evidence of response to disease progression or death, whichever comes first) and safety.

Cohort B: Eligible patients will receive camrelizumab (200mg q3w iv) plus apatinib (250 mg qd po) plus chemotherapy. Treatment will be continued until disease progression, unacceptable toxicity, or withdrawal of consent. Patients will receive 6 cycles of consolidation therapy if achieving a complete response. The primary endpoint is objective response rate. Secondary endpoints include progression-free survival, duration of response, overall survival and safety.

• Study Type: Interventional
• Enrollment (Anticipated): 73
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yang Xiang; Phone Number: 010-69156068; Email: XiangY@pumch.cn

Study Locations

• China
  • Beijing, China
    • Recruiting
    • Peking Union Medical College Hospital
    • Contact: xiang yang

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Woman aged 18-60 years;
2. Previously untreated patients with ultra high-risk GTN（Cohort A） or high-risk chemo-refractory or relapsed GTN (Cohort B);
3. No previous chemotherapy or radiotherapy for ultra high-risk GTN（Cohort A）and have previously received two or more lines of combination chemotherapies for high-risk chemo-refractory or relapsed GTN (Cohort B);
4. Patients with ultra high-risk GTN (FIGO stages I-III: score ≥13 and stage IV) according to the International Federation of Gynecology and Obstetrics (FIGO) 2000 staging and risk factor scoring system（Cohort A）and patients with a prognostic score ≥7 (Cohort B);
5. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;
6. Patients with abnormal serum hCG level (≥5 IU/L);
7. Expected survival ≥ 4 months;

8. The function of vital organs meets the following requirements:

   hemoglobin ≥90 g/L, absolute neutrophil count ≥1·5×109/L, platelets ≥100×109/L; creatinine ≤1·5 × upper limit of normal (ULN), urea nitrogen ≤2·5×ULN; total bilirubin ≤ULN, alanine aminotransferase and aspartate aminotransferase ≤2·5×ULN, albumin ≥25 g/L; thyroid stimulating hormone ≤ULN (if thyroid stimulating hormone is abnormal, normal T3 and T4 can also be acceptable).

9. Female patients of childbearing age must exclude pregnancy and are willing to use a medically approved high-efficiency contraceptive (e.g., intrauterine device, contraceptive or condom) during the study period and within 6 months of the last study drug administration.
10. The patient should be aware of the purpose of the study and the operations required by the study and volunteer to participate in the study before sign the informed consent form.

Exclusion Criteria:

1. Previous treatment with immunotherapy drugs (including antibodies targeting PD-1, PD-L1, cytotoxic T-lymphocyte-associated protein 4, T-cell receptor, chimeric antigen receptor T-cell therapy, and other immunotherapy), anti-angiogenic small-molecule tyrosine kinase inhibitors (such as pazopanib, sorafenib, or regorafenib), or anti-angiogenic monoclonal antibodies (such as bevacizumab); live vaccines injected within 4 weeks before the first dose of study drug; other clinical trials of antitumour drugs within 4 weeks before the first dose of study drug;
2. Other malignancies in the past 3 years;
3. Immunosuppressive drugs used within 14 days prior to the first dose of camrelizumab; any active autoimmune disease or a history of autoimmune disease;
4. Uncontrollable hypertension (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg, despite with the optimal drug therapy);
5. Grade II or higher myocardial ischemia, myocardial infarction or poorly controlled arrhythmia (females with QTc interval ≥470 ms); grade III to IV cardiac insufficiency according to New York Heart Association (NYHA) criteria, or cardiac color Doppler ultrasound evidence of left ventricular ejection fraction <50%; myocardial infarction, NYHA grade II or above heart failure, uncontrolled angina, uncontrolled severe ventricular arrhythmia, clinically significant pericardial disease, or electrocardiogram suggesting acute ischemia or abnormal active conduction system occurring within 6 months before enrolment;
6. Abnormal coagulation (international normalised ratio >1·5×ULN or prothrombin time >ULN+4 seconds or activated partial thromboplastin time >1·5×ULN), with bleeding tendency or undergoing thrombolysis or anticoagulant therapy;
7. Severe infections within 4 weeks prior to the first dose of study drug (e.g., need of intravenous infusion of antibiotics, antifungal or antiviral drugs), or unexplained fever (>38·5°C) during screening or the first dose of study drug;
8. With a history of psychotropic drug abuse and are unable to withdraw the psychotropic drug, or have mental disorders;
9. Major surgery performed within 4 weeks before the first dose of study drug, or open wounds or fractures;
10. Obvious factors affecting oral drug absorption, such as inability to swallow, chronic diarrhea and intestinal obstruction, or sinus or perforation of empty organs within 6 months;
11. Routine urine test indicating urinary protein ++ or more, or confirmed urinary protein ≥1·0 g within 24 hours;
12. Human immunodeficiency virus infection or known acquired immunodeficiency syndrome, active hepatitis B (HBV DNA >500 IU/mL), hepatitis C (hepatitis C antibody positive, and HCV-RNA higher than the lower limit of the analysis method) or co-infection with hepatitis B and hepatitis C;
13. Other reasons as judged by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A; Population: ultra high-risk gestational trophoblastic neoplasia	Drug: Camrelizumab plus apatinib CohortA; Cohort A: Camrelizumab (200 mg q2w iv) concomitantly with apatinib (250 mg qd po) and EMA/CO [etoposide, methotrexate, actinomycin D/cyclophosphamide, vincristine] every 2 weeks. For certain patients with high tumor burden, 1-2 cycles of low-dose chemotherapy (actinomycin D 500 ug and etoposide 100mg/m2, D1-3) will be administered, then followed by EMA/CO. The observation period is 14 days.; Other Names: Camrelizumab plus apatinib and multi-drug chemotherapy
Experimental: Cohort B; Population: high-risk chemo-refractory or relapsed gestational trophoblastic neoplasia	Drug: Camrelizumab plus apatinib Cohort B; Cohort B: Camrelizumab (200 mg q3w iv) concomitantly with apatinib (250 mg qd po) and multi-drug chemotherapy. The multi-drug chemotherapy regimen will be chosen by the investigator (chemotherapy regimen: EMA/CO [etoposide, methotrexate, actinomycin D/cyclophosphamide, vincristine]; or EMA/EP [etoposide, methotrexate and actinomycin-D/etoposide, cisplatin]; or FAEV [floxuridine, actinomycin-D, etoposide, vincristine]). The observation period is 21 days.; Other Names: Camrelizumab plus apatinib and multi-drug chemotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohort A: Complete remission rate	The proportion of patients achieving complete remission. Complete remission is defined as normal serum β-hCG level measured for 3 consecutive weeks.	up to one year
Cohort B: Objective response rate	The proportion of patients with complete or partial response according to serum β-hCG level. Partial response is defined as a ≥50% decrease in β-hCG level from baseline after 2 cycles.	up to one year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohort A: Objective response rate	The proportion of patients with complete or partial response according to serum β-hCG level.	up to one year
Cohort A: Progression-free survival	The time from the treatment initiation to disease progression or death, whichever comes first. Disease progression is defined as any increase in serum β-hCG level from baseline after 2 cycles of treatment or the presence of new metastatic lesions.	up to one year
Cohort A: Overall survival	The time from the treatment initiation to the date of death or last follow-up.	up to one year
Cohort A: Duration of response	The time from the first evidence of response to disease progression or death, whichever comes first.	up to one year
Cohort A: Frequency and severity of adverse events	Determine frequency and severity of adverse events as assessed by NCI CTCAE (Version 5.0) which is used to evaluate the grade of adverse events, to observe any adverse event and serious adverse event that occurred in all patients during the clinical study period, including abnormal laboratory examination results, clinical manifestations and vital signs, to record their clinical manifestation characteristics, severity, occurrence time, duration, corresponding treatment and prognosis, and to determine their relationship with the study drug.	up to one year
Cohort B: Progression-free survival	The time from the treatment initiation to disease progression or death, whichever comes first.	up to one year
Cohort B: Duration of response	The time from the first evidence of response to disease progression or death, whichever comes first.	up to one year
Cohort B: Overall survival	The time from the treatment initiation to the date of death or last follow-up.	up to one year
Cohort B: Frequency and severity of adverse events	Determine frequency and severity of adverse events as assessed by NCI CTCAE (Version 5.0) .	up to one year

Collaborators and Investigators

• Sponsor: Peking Union Medical College Hospital
• Collaborators: Jiangsu HengRui Medicine Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2022
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): June 1, 2024

Study Registration Dates

• First Submitted: November 6, 2021
• First Submitted That Met QC Criteria: November 24, 2021
• First Posted (Actual): December 1, 2021

Study Record Updates

• Last Update Posted (Actual): July 11, 2022
• Last Update Submitted That Met QC Criteria: July 7, 2022
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms, Germ Cell and Embryonal; Pregnancy Complications; Pregnancy Complications, Neoplastic; Trophoblastic Neoplasms; Neoplasms; Gestational Trophoblastic Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Apatinib
• Other Study ID Numbers: MA-GTN-II-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No