ProTarget - A Danish Nationwide Clinical Trial on Targeted Anti‐Cancer Treatment based on Genomic Profiling

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Rigshospitalet

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

1 Sep 2020 → ongoing

Decision date (initial)

2024-05-16

Transition trial

Yes

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-510527-29-00

EudraCT number

2019-004771-40

ClinicalTrials.gov

NCT04341181

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To describe in different types of population the anti‐tumor activity (efficacy, measured as ORR at 16 weeks) and toxicity (safety) of commercially available, targeted anti‐cancer drugs used for treatment of patients with advanced disease with a genomic variant known (i) to be a target of an EMA‐approved anti‐cancer drug or (ii) to predict sensitivity to an EMA‐approved anti‐cancer drug.

Secondary objectives 3

1. To record the site investigator determination treatment‐related adverse events experienced by patients receiving treatment with commercially available, targeted anti‐cancer drugs.
2. To perform refined biomarker analyses, including (but not limited to) whole genome sequencing, on a fresh tumor biopsy specimen at baseline and at progression.
3. To study mechanisms of resistance by the use of serial fresh tumor biopsies for WGS and liquid biopsi.

Conditions and MedDRA coding

Cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 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.
2. ECOG performance status 0-2
3. 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..
4. 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.
5. 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.
6. Ability to understand and the willingness to sign a written informed consent/assent document
7. 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.
8. For orally administered drugs, the patient must be able to swallow and tolerate oral medication and must have no known malabsorption syndrome
9. 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 14

1. 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.
2. Previous treatment with the selected study drug for the same malignancy.
3. 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.
4. 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.
5. Female patients who are pregnant or nursing. Male and female patients who refuse to practice highly effective contraception methods.
6. 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
7. Patients with preexisting cardiac conditions, including uncontrolled or symptomatic angina, uncontrolled atrial or ventricular arrhythmias, or symptomatic congestive heart failure are not eligible.
8. Patients with left ventricular ejection fraction (LVEF) known to be < 40% are not eligible.
9. Patients with stroke (including TIA) or acute myocardial infarction within 4 months before the first dose of study treatment are not eligible
10. Patients with acute gastrointestinal bleeding within 1 month of start of treatment are not eligible.
11. 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.
12. Patients who do not meet drug‐specific eligibility requirements for the drug selected by the investigator, are not eligible to receive that drug.
13. Patients whose disease is not measurable or assessable by radiographic imaging or physical examination (e.g., elevated serum tumor marker only) are not eligible.
14. Patients with known allergy/hypersensitivity to the study drug (active substance or to any of the excipients).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Anti-tumor activity, as assessed by objective response at 16 weeks
2. Stable disease at 16 weeks
3. Treatment-related and serious adverse events

Secondary endpoints 5

1. Duration of response, progression-free and overall survival
2. Duration of treatment on study (time on drug)
3. Percentage of patients that are treated based on their molecular tumor profile
4. Description of concordance between mutational profile of pre-treatment tumor biopsies and mutational profile according to tumor profiling tests that were used to enroll patients
5. Identification of patterns of resistance based on serial tumor biopsies and liquid biopsies

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 10

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Rigshospitalet

Sponsor organisation

Rigshospitalet

Address

Blegdamsvej 9

City

Copenhagen Oe

Postcode

2100

Country

Denmark

Scientific contact point

Organisation

Rigshospitalet

Contact name

Sponsor

Public contact point

Organisation

Rigshospitalet

Contact name

Sponsor

Third parties 1

Locations

1 EU/EEA country · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 33 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications