Evaluation of Targeted Anti-Cancer Therapy Using Vemurafenib and Drug Combinations in Patients with Advanced Cancer and Genomic Variants
- Trial ID
- 2023-510527-29-00
- Sponsor
- Region Hovedstaden
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to evaluate the **anti-tumor activity** and **toxicity** of commercially available, targeted anti-cancer drugs in patients with advanced cancer. The efficacy is measured as the objective response rate (ORR) at 16 weeks, and the safety is assessed by monitoring toxicity. This is clinically relevant as it aims to determine the effectiveness and safety of these drugs in patients with genomic variants that are either targets of or predict sensitivity to EMA-approved anti-cancer drugs.
Secondary objectives include:
- Recording treatment-related adverse events as determined by site investigators.
- Performing refined biomarker analyses, such as whole genome sequencing, on fresh tumor biopsy specimens at baseline and at progression.
- Studying mechanisms of resistance using serial fresh tumor biopsies for whole genome sequencing and liquid biopsies.
Participants
The clinical trial involves participants diagnosed with **cancer**, specifically those with locally advanced or metastatic malignant disease. The study population includes both male and female subjects aged 18 years and older. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, indicating they are fully active or capable of self-care but unable to carry out any work activities. The trial does not involve a vulnerable population. Participants must have acceptable organ function and measurable or evaluable disease as per RECIST v1.1 criteria. The trial population was selected based on the presence of a tumor genomic profile that suggests potential clinical benefit from approved targeted anti-cancer therapies. Participants must be able to swallow oral medication and have no known malabsorption syndrome. Lifestyle considerations include the requirement for effective contraception for both men and women of child-bearing potential due to the risks of drug treatment to a developing fetus. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed to evaluate the **anti-tumor** activity and safety of various **targeted anti-cancer drugs** in patients with advanced cancer who have a genomic variant that is either a target of an EMA-approved drug or predicts sensitivity to such a drug. The trial employs a **randomized, double-blind, controlled** design to ensure the reliability and validity of the results. The estimated duration of the trial is from July 2024 to July 2029, with participant involvement expected to last up to 999 days, depending on the specific drug regimen and patient response.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, organ function, and genomic profile. Following successful screening, participants will be randomized to receive one of the study drugs, which include **vemurafenib**, **axitinib**, **trastuzumab emtansine**, **selpercatinib**, **olaparib**, **pertuzumab**, **alectinib hydrochloride**, **atezolizumab**, **avelumab**, **cobimetinib**, **trastuzumab**, **vismodegib**, **pemigatinib**, and **niraparib tosilate monohydrate**. These drugs are administered either orally or via intravenous infusion, depending on the formulation.
Study visits will occur at regular intervals to monitor the **objective response rate (ORR)** at 16 weeks, assess stable disease, and document any treatment-related adverse events. Secondary endpoints include the duration of response, progression-free survival, overall survival, and the percentage of patients treated based on their molecular tumor profile. The trial will also explore the concordance between pre-treatment tumor biopsies and tumor profiling tests, as well as patterns of resistance through serial biopsies.
The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the overall treatment efficacy and safety. Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they choose to withdraw consent. Additionally, female participants who become pregnant must discontinue treatment immediately. The trial aims to provide valuable insights into the effectiveness of targeted therapies in a genomically defined patient population.
Treatment
The clinical trial involves the administration of several **experimental medications**. **Zelboraf** 240 mg film-coated tablets, containing the active substance **vemurafenib**, are administered orally. The maximum daily dose is 1920 mg, and the treatment period can extend up to 999 days. **Inlyta** is available in multiple dosages: 7 mg, 5 mg, 3 mg, and 1 mg film-coated tablets, all containing **axitinib**. These are also administered orally with a maximum daily dose of 10 mg. **Retsevmo** 40 mg hard capsules, containing **selpercatinib**, are administered orally with a maximum daily dose of 220 mg. **Lynparza** is available in 150 mg and 100 mg film-coated tablets, containing **olaparib**, administered orally with a maximum daily dose of 600 mg. **Alecensa** 150 mg hard capsules, containing **alectinib hydrochloride**, are administered orally with a maximum daily dose of 1200 mg. **Cotellic** 20 mg film-coated tablets, containing **cobimetinib**, are administered orally with a maximum daily dose of 60 mg. **Erivedge** 150 mg hard capsules, containing **vismodegib**, are administered orally with a maximum daily dose of 150 mg. **Pemazyre** 4.5 mg tablets, containing **pemigatinib**, are administered orally with a maximum daily dose of 13.5 mg. **Zejula** 100 mg hard capsules, containing **niraparib tosilate monohydrate**, are administered orally with a maximum daily dose of 300 mg.
**Kadcyla** is available in 160 mg and 100 mg powder for concentrate for solution for infusion, containing **trastuzumab emtansine**. It is administered via **intravenous administration** with a maximum daily dose of 3.6 mg/kg. **Perjeta** 420 mg concentrate for solution for infusion, containing **pertuzumab**, is administered intravenously with a maximum daily dose of 840 mg. **Tecentriq** 1200 mg concentrate for solution for infusion, containing **atezolizumab**, is administered via intravenous infusion with a maximum daily dose of 1680 mg. **Bavencio** 20 mg/mL concentrate for solution for infusion, containing **avelumab**, is administered intravenously with a maximum daily dose of 800 mg. **Herceptin** 150 mg powder for concentrate for solution for infusion, containing **trastuzumab**, is administered via intravenous administration with a maximum daily dose of 8 mg/kg.
All medications are administered according to the specified dosing schedules, and participant compliance is monitored throughout the trial. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The pharmaceutical forms, routes of administration, and dosing regimens are designed to optimize the therapeutic potential of each investigational product while ensuring participant safety.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of anti-tumor activity, measured as the **objective response rate (ORR)** at 16 weeks. Additional primary endpoints include the assessment of stable disease at 16 weeks and the monitoring of treatment-related and serious adverse events. Secondary endpoints will focus on the duration of response, progression-free survival, overall survival, and the duration of treatment on study (time on drug). The trial will also evaluate the percentage of patients treated based on their molecular tumor profile and describe the concordance between the mutational profile of pre-treatment tumor biopsies and the mutational profile according to tumor profiling tests used for patient enrollment. Furthermore, patterns of resistance will be identified based on serial tumor biopsies and liquid biopsies.
The trial will utilize genomic profiling to determine the eligibility of patients, ensuring that participants have a tumor genomic profile that suggests potential clinical benefit from the approved targeted anti-cancer therapies included in the study. The efficacy assessments will be conducted at specified intervals, with the primary endpoint being evaluated at the 16-week mark. The trial is designed to provide comprehensive data on the efficacy of targeted anti-cancer drugs in patients with advanced disease, leveraging genomic variants known to be targets of EMA-approved drugs or predictive of sensitivity to such drugs.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient (age≥ 18 years) with a histologically proven locally advanced or metastatic malignant disease who is no longer benefitting from standard anti‐cancer treatment or for whom, in the opinion of the investigator, no such treatment is available or indicated.
- ECOG performance status 0-2
- Patients must have acceptable organ function as defined below. However, as noted above, drugspecific inclusion/exclusion criteria specified in the appendix for each agent will take precedence for this and all inclusion criteria: a) Absolute neutrophil count ≥ 1500 μl b) Hemoglobin > 5.6 mmol/l c. Platelets > 75,000/μl d) Total bilirubin < 1.5 x institutional upper limit of normal (ULN) e) AST (SGOT) and/or ALT(SGPT) < 2.5 x institutional upper limit of normal (ULN) (or < 5 x ULN in patients with known hepatic metastases) f) Calculated or measured creatinine clearance ≥ 50 mL/min/1.73 m2 and/or creatinine ≤ 1.5 x ULN..
- Patients must have measurable or evaluable disease (per RECIST v1.1 for solid tumor), defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non‐nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or a subcutaneous or superficial lesion that can be measured with calipers by clinical exam. For lymph nodes, the short axis must be ≥15 mm. Patients who have assessable disease by physical or radiographic examination but do not meet these definitions of measurable disease are eligible and will be considered to have evaluable disease. Patient’s whose disease cannot be objectively measured by physical or radiographic examination (e.g., elevated serum tumor marker only) are NOT eligible, with the exception of CA‐125 for ovarian cancer and PSA for prostate cancer.
- Results must be available from a genomic test or immunohistochemistry (IHC) test for protein expression performed in a laboratory accredited by the competent local regulatory authority. The genomic or IHC test used to qualify a patient for participation in ProTarget may have been performed on any specimen of the patient’s tumor obtained at any point during the patient’s care at the discretion of the patient’s treating physician. Genomic assays performed on cell‐free DNA in plasma (“liquid biopsies”) will also be acceptable if the genomic analysis is performed in a laboratory accredited by the competent local regulatory authority. A new biopsy must be performed if possible, for central confirmation by WGS (the result may be awaited and is not required before first dosing). Note: Eligible genomic tests may include any of the following technologies: fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), comparative genomic hybridization (CGH), next generation sequencing (NGS), whole exome sequencing (WES). The test may have been performed on a fresh (frozen or in RNA‐later) or paraffin‐embedded specimen of the primary tumor or a metastatic deposit or on cell free DNA derived from plasma, as determined by the treating physician, and must reveal a potentially actionable genomic variant as defined in Section 5.0, or protein overexpression by IHC.
- Ability to understand and the willingness to sign a written informed consent/assent document
- Have a tumor genomic profile for which treatment with one of the approved targeted anti‐cancer therapies included in this study has potential clinical benefit based on the criteria described in Section 7.0.
- For orally administered drugs, the patient must be able to swallow and tolerate oral medication and must have no known malabsorption syndrome
- Because of the risks of drug treatment to the developing fetus, women of child‐bearing potential and men must agree to use highly effective contraception (hormonal or barrier method of birth control; abstinence) in combination with inhibition of ovulation (intrauterine device (IUD), intrauterine hormone‐releasing system ( IUS), bilateral tubal occlusion, vasectomized partner or sexual abstinence) for the duration of study participation, and for four to 24 months following completion of study therapy (depending on SPC from individual drugs). Should a woman become pregnant or suspect she is pregnant while participating in this study or if she is the partner of a male participant in this study and becomes pregnant while he is participating in this study, she should inform her or her partner’s treating physician immediately as well as her obstetrician. Female study patients who become pregnant must immediately discontinue treatment with any study therapy. Male patients should avoid impregnating a female partner. Male study patients, even if surgically sterilized, (i.e., post‐vasectomy) must agree to one of the following: practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or completely abstain from sexual intercourse.
Exclusion Criteria
- Ongoing toxicity > CTCAE grade 2, other than peripheral neuropathy, related to anti‐tumor treatment that was completed within 4 weeks prior to registration. Patients with ongoing peripheral neuropathy of ≥ CTCAE grade 3 will be excluded.
- Previous treatment with the selected study drug for the same malignancy.
- If the patient’s tumor has a genomic variant known to confer resistance to an anti‐cancer agent available in this study, the patient will not be eligible to receive that agent but will be eligible to receive other drugs available in this study if all inclusion and exclusion criteria are met for that drug.
- Patient is receiving any other anti‐cancer therapy (cytotoxic, biologic, radiation, or hormonal other than for replacement) ≤28 days or 5 half‐lives, whichever is shorter, or ≤ 6 weeks for cytotoxic agents with major delayed toxicities (such as nitrosoureas and mitomycin C) before the planned first dose of study drug. Medications that are prescribed for supportive care but may potentially have an anti‐cancer effect (e.g., megestrol acetate, bisphosphonates, zoledronic acid, RANK‐L inhibitors) or antihormonal therapies are allowed during screening and treatment provided that treatment with these agents have been initiated >28 days before C1D1. Patients may be on warfarin, low molecular weight heparin or direct factor Xa inhibitors, unless such therapies are prohibited by drug‐specific exclusion criteria.
- Female patients who are pregnant or nursing. Male and female patients who refuse to practice highly effective contraception methods.
- Patients with known progressive brain metastases determined by serial imaging or declining neurologic function in the opinion of the treating physician are not eligible. Patients with previously treated brain metastases are eligible, provided that the patient has not experienced a seizure or had a clinically significant change in neurological status within the 3 months prior to registration. All patients with previously treated brain metastases must be clinically stable for at least 1 month after completion of treatment and off steroid treatment for one month prior to study enrollment. For GBM, a maximum of 10 mg corticosteroid stable for at least one week is allowed. Specific exclusion criteria for GBM patients: a. Patients who require anti‐convulsant therapy must be taking non‐enzyme inducing antiepileptic drugs (non‐EIAED), if the selected targeted drug is a substrate of CYP3A4. Patients previously on EIAED must be switched to non‐ EIAED at least 2 weeks prior to randomization. b. No radiotherapy within the three months prior to the diagnosis of progression. c. No radiotherapy with a dose over 65 Gy, stereotactic radiosurgery or brachytherapy unless the recurrence is histologically proven
- Patients with preexisting cardiac conditions, including uncontrolled or symptomatic angina, uncontrolled atrial or ventricular arrhythmias, or symptomatic congestive heart failure are not eligible.
- Patients with left ventricular ejection fraction (LVEF) known to be < 40% are not eligible.
- Patients with stroke (including TIA) or acute myocardial infarction within 4 months before the first dose of study treatment are not eligible
- Patients with acute gastrointestinal bleeding within 1 month of start of treatment are not eligible.
- Patients with any other clinically significant medical condition which, in the opinion of the treating physician, makes it undesirable for the patient to participate in the study or which could jeopardize compliance with study requirements including, but not limited to: ongoing or active infection, significant uncontrolled hypertension, severe psychiatric illness situations, or anticipated or planned anti‐cancer treatment or surgery.
- Patients who do not meet drug‐specific eligibility requirements for the drug selected by the investigator, are not eligible to receive that drug.
- Patients whose disease is not measurable or assessable by radiographic imaging or physical examination (e.g., elevated serum tumor marker only) are not eligible.
- Patients with known allergy/hypersensitivity to the study drug (active substance or to any of the excipients).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Recruiting | 15 Jul 2024 | 600 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Lynparza 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 600 | 999 | PRD6163467 |
Herceptin 150 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS ADMINISTRATION | 8 | 999 | PRD2159200 |
Zejula 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 300 | 999 | PRD9709363 |
Perjeta 420 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS ADMINISTRATION | 840 | 999 | PRD2154581 |
Pemazyre 4.5 mg tablets | Test | TABLETS | ORAL | 13.5 | 999 | PRD8840284 |
Lynparza 150 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 600 | 999 | PRD6152224 |
Cotellic 20 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 60 | 999 | PRD3439656 |
Zelboraf 240 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 1920 | 999 | PRD2154737 |