RC48 Monotherapy or Combination With Envafolimab for CDK12 Alterations mCRPC With Standard Treatment Failure

Prospective, Single Arm, Multi Cohort Clinical Study of Disitamab Vedotin(RC48) Monotherapy or Combination With Envafolimab for Second-line Treatment of CDK12 Alterations Metastatic Castration Resistant Prostate Cancer With Standard Treatment Failure

The aim of this study is to evaluate the efficacy and safety of vediximab monotherapy or in combination with enrolizumab for second-line treatment of CDK12 alterations mCRPC that has failed standard therapy. The research results are expected to provide new insights and breakthroughs for the treatment of advanced prostate cancer.

Study Overview

• Status: Recruiting
• Conditions: Prostate Cancer; CDK12 Gene Mutation
• Intervention / Treatment: Drug: RC48; Drug: Envafolimab

Detailed Description

This study plans to enroll 72 mCRPC patients who have failed at least one NHT standard treatment and have exhausted PARPi treatment (such as AVPC/NEPC, requiring platinum chemotherapy resistance or intolerance). The patient carries CDK12 mutation combined with ERBB amplification (NGS or FISH) or HER2 IHC (1+, 2+, 3+). The enrolled patients were divided into queue A and queue B based on whether they carried potential immunotherapy adverse factors (including chromosome instability mutation profiles such as 11q13 co amplification, MDM2/4 amplification, FGFRs amplification, etc.). During the treatment phase of patients in queue A (excluding CDK12mut from mutation spectrum features in queue B), subjects received intravenous infusion of vediximab (2.0 mg/kg) every 2 weeks, in combination with subcutaneous injection of bevacizumab (400 mg) every 3 weeks, until disease progression or death occurred. During the treatment phase, subjects in queue B (CDK12mut combined with 11q13 co amplification, MDM2/4 amplification, FGFRs amplification and other chromosomal unstable mutation profiles) received intravenous infusion of vediximab (2.0 mg/kg) every 2 weeks until disease progression or death occurred. The main endpoint of the study was hierarchical testing, Step 1: ORR in CDK12 mut mCRPC with ERBB2 IHC 3+or FISH+or ERBB amplification (CN ≥ 4); Step2: ORR in ITT。 The secondary endpoints of the study include PSA50, PFS, OS, and safety.

• Study Type: Interventional
• Enrollment (Estimated): 72
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Haitao Wang, Ph.D; Phone Number: +86-022-88326385; Email: peterrock2000@126.com
• Study Contact Backup: Name: Jinhuan Wang, Ph.D; Phone Number: +86-022-88326610; Email: wjhhappy2008@163.com

Study Locations

• China
  • Tianjin
    • Tianjin, Tianjin, China, 300211
      • Recruiting
      • Tianjin Medical Unversity Second Hospital
      • Sub-Investigator: Lili Wang
      • Sub-Investigator: Dingkun Hou
      • Principal Investigator: Haitao Wang
      • Sub-Investigator: Jinhuan Wang
      • Contact: Haitao Wang; Phone Number: +86-02288326610; Email: peterrock2000@126.com
      • Contact: Lili Wang; Phone Number: +86-13516108466; Email: wangliliaigang@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Participants must be able to understand the procedures and methods of this study, willing to strictly follow the clinical trial protocol to complete the trial, and voluntarily sign a written informed consent form;
2. Patients aged ≥ 18 years old;
3. Pathological examination confirms non resectable or metastatic HER2 positive castration resistant prostate cancer (mCRPC): HER2 positive is defined as IHC 3+or IHC 2+or FISH+;
4. Carrying CDK12 mutation combined with ERBB amplification (NGS or FISH) or HER2 IHC (1+, 2+, 3+);
5. According to the RECIST solid tumor efficacy evaluation criteria, there must be at least one measurable lesion;
6. ECOG PS: 0-2 points;
7. Expected survival period is not less than 12 weeks;
8. Prior exposure to at least one novel endocrine therapy (including abiraterone, enzalutamide, darotamine, apatamide, and rivalutamide) and depletion of PARPi treatment (if AVPC/NEPC, platinum chemotherapy resistance or intolerance is required);
9. Have not used HER2 targeted drugs (including antibodies, small molecule TKIs, and antibody drug conjugates);
10. The main organ functions are normal, which meets the following criteria:

1) The standard for blood routine examination should meet the requirement of: Hb ≥ 90g/L (no blood transfusion or blood products within 14 days, no correction with G-CSF or other hematopoietic stimulating factors); ANC≥1.5×109/L； PLT≥90×109/L； 2) Biochemical tests must meet the following standards: TBiL≤1×ULN； ALT and AST ≤ 1.5 × ULN; ALP≤2.5×ULN； BUN and Cr ≤ 1.5 × ULN; 3) Cardiac ultrasound: Left ventricular ejection fraction (LVEF) ≥ 50%; 11. The subjects voluntarily joined this study, signed an informed consent form, had good compliance, and cooperated with follow-up.

Exclusion Criteria:

1. Individuals with a known history of allergies to the components of this medication regimen;
2. Have other malignant tumors within the past 5 years prior to signing the informed consent form (excluding non melanoma skin cancer or other tumors that have been effectively treated, and malignant tumors that are considered cured);
3. Existence of brain metastases and/or cancerous meningitis;
4. Previously received allogeneic stem cell or parenchymal organ transplantation;
5. Past or current congenital or acquired immunodeficiency diseases;
6. Patients who are known or suspected to have a history of allergies to vediximab or paclitaxel like drugs, or who have a history of hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins, or who are allergic to excipients of the study drug;
7. Other significant clinical and laboratory abnormalities, which the researchers believe will affect the safety evaluation, such as uncontrollable diabetes, hypertension, cirrhosis, interstitial pneumonia, obstructive pulmonary disease, chronic kidney disease, peripheral neuropathy of grade II or above (CTCAE V5.0), thyroid dysfunction, heart failure of NYHA grade 3 or above, etc;

8. Severe infections that are active or poorly controlled clinically; Active infections, including:

   1. AIDS virus (HIV/2 antibody) positive;
   2. Active hepatitis B (HBsAg positive or HBV DNA>2000IU/ml with abnormal liver function);
   3. Active hepatitis C (HCV antibody positive or HCV RNA ≥ 103 copies/ml with abnormal liver function);
   4. Active tuberculosis;
   5. Other uncontrollable active infections (CTCAE V5.0>grade 2);
9. Severe heart disease or discomfort that cannot be treated;
10. Suffering from mental illness or substance abuse, unable to cooperate;
11. Simultaneously participating in other clinical trials;
12. The researchers believe that it is not suitable for the participants to be included.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A; During the treatment phase of patients in cohort A (excluding CDK12 alterations from mutation spectrum features in cohort B), subjects received intravenous infusion of Disitamab Vedotin(RC48) (2.0 mg/kg) every 2 weeks, in combination with subcutaneous injection of Envafolimab (400 mg) every 3 weeks, until disease progression or death occurred.	Drug: RC48; During the patient treatment phase, the subjects received intravenous infusion of Disitamab Vedotin(RC48) (2.0 mg/kg) every 2 weeks until disease progression or death occurred.; Other Names: Disitamab Vedotin; Drug: Envafolimab; During the treatment phase of the patient, the subjects received subcutaneous injections of Envafolimab (400 mg) every 3 weeks until the patient experienced disease progression or death.
Experimental: Cohort B; During the treatment phase, subjects in cohort B (CDK12 alterations combined with 11q13 co-amplification, MDM2/4 amplification, FGFRs amplification and other chromosomal unstable mutation profiles) received intravenous infusion of Disitamab Vedotin(RC48) (2.0 mg/kg) every 2 weeks until disease progression or death occurred.	Drug: RC48; During the patient treatment phase, the subjects received intravenous infusion of Disitamab Vedotin(RC48) (2.0 mg/kg) every 2 weeks until disease progression or death occurred.; Other Names: Disitamab Vedotin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prostate Specific Antigen (PSA) ≥50% Response Rate (PSA50)	Will assess PSA decline of ≥50% from baseline (PSA50), using the Prostate Cancer Working Group 3 (PCWG3) criteria.	From treatment administration up to a maximum duration of 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	Objective Response Rate (ORR) assessed according to the evaluation criteria for the efficacy of solid tumors (RECIST v1.1).	Up to approximately 3 years
Progression Free Survival(PFS)	The time from the beginning of the patient's treatment to the disease progression or death for any reason.Based on RECIST criteria v1.1	From treatment administration up to a maximum duration of 36 months
Overall Survival(OS)	Time from start of treatment to death due to any cause.	From treatment administration up to a maximum duration of 36 months
Percentage of Participants With Adverse Events (AEs)	Number of participants with adverse effects of treatment. Frequency and severity of adverse effects of treatment as assessed by NCI CTCAE v5.0	Up to approximately 3 years

Collaborators and Investigators

• Sponsor: Tianjin Medical University Second Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 24, 2024
• Primary Completion (Estimated): May 31, 2027
• Study Completion (Estimated): August 31, 2027

Study Registration Dates

• First Submitted: October 26, 2024
• First Submitted That Met QC Criteria: October 26, 2024
• First Posted (Actual): October 29, 2024

Study Record Updates

• Last Update Posted (Actual): October 29, 2024
• Last Update Submitted That Met QC Criteria: October 26, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Prostatic Neoplasms; Immunologic Factors; Physiological Effects of Drugs; Immunoconjugates; Disitamab vedotin
• Other Study ID Numbers: RC48-mCRPC

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