CRAFT: The NCT-PMO-1602 Phase II Trial

  • STATUS
    Recruiting
  • End date
    Apr 1, 2024
  • participants needed
    175
  • sponsor
    German Cancer Research Center
Updated on 8 April 2022

Summary

Whole-genome and transcriptome sequencing of patients with advanced solid tumors enrolled in the NCT/DKTK MASTER (Molecularly Aided Stratification for Tumor Eradication Research) program revealed genetic alterations in a substantial proportion of patients including (i) alterations that lead to aberrant activation of BRAF, ERBB2, ALK, and the PI3K-AKT and MAPK pathways and (ii) changes that predict sensitivity to immune checkpoint inhibition, such as high tumor mutational burden and specific alterations of the PD-L1 locus.

Within this seven-arm basket phase II clinical trial, we aim to investigate the efficacy of targeted-therapy plus immune checkpoint inhibition in patients with advanced tumors exhibiting one of the following genetic alterations detected within the NCT/DKTK MASTER study: (i) BRAF V600E/K, (ii)ERBB2 amplification and/or overexpression or activating ERBB2 mutation, (iii) ALK rearrangement or activating ALK mutation, (iv) activating PIK3CA or AKT mutations or other aberration predicting increased PI3K-AKT pathway activity, (v) abberations predicting increased RAF-MEK-ERK pathway activity; (vi) patients with high tumor mutational burden and/or specific alteration predicting sensitivity to PD-1/PD-L1 inhibition are eligible within this study for immune checkpoint inhibition. Recruitment of adequate patient numbers into these well-defined molecular subgroup is achieved in a multicenter approach including NCT Heidelberg and NCT Dresden as well as DKTK partner sites. Eligible patients will be identified by in-depth molecular characterization of tumors within the NCT/DKTK MASTER program. All study arms are based on similar biometrical assumptions, and sample size as well as power calculations are based on Simon's optimal two-stage design for each study arm separately. The overall aim is to reduce the cumulative hazard of progression-free survival observed within the study (PFS2) compared to the cumulative hazard of the progression-free time before inclusion into the study (PFS1) using a paired log-rank test. The sample size of the entire trial varies according to the performance of the individual study arms, ranging between 98 and 175 patients.

Details
Condition Metastatic or Locally Advanced Malignancies
Treatment Trastuzumab, Pertuzumab, Vemurafenib, Cobimetinib, Alectinib, Atezolizumab, Ipatasertib
Clinical Study IdentifierNCT04551521
SponsorGerman Cancer Research Center
Last Modified on8 April 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Provision of written informed consent
Ability of patient to understand and comply with the protocol for the duration of the study, including treatment and scheduled visits and examinations
Diagnosis of a metastatic or locally advanced malignancy
Progressive disease
At least one measurable lesion that can be accurately assessed at baseline by computed tomography or magnetic resonance imaging and is suitable for repeated assessment
Prior administration of at least one standard chemotherapy for primary and/or relapsed malignancy according to current guidelines. Patients must have received standard therapy or have no standard therapy available. Or, in the opinion of investigator have been considered ineligible for a particular form of standard therapy on medical reasons
ECOG Performance Status ≤2
Age ≥18 years, no upper age limit
Postmenopausal or evidence of non-childbearing status
Female patients of childbearing potential and male patients with partners of childbearing potential who are sexually active must agree to the use of two highly effective forms of contraception. These should be started immediately after signing the informed consent form and continued throughout the period of study treatment plus at least seven months for both sexes after taking the last dose of study drug
Availibility of complete information about the last medical treatment given before study participation, i.e. remission status before start of treatment, dosage and timing of drugs applicated, remission status and date of progression after treatment (in order to calculate PFS 1)
For patients included on the basis of molecular testing other than NCT/DKTK MASTER and for patients with an analysis in NCT/DKTK MASTER performed more than 3 months (date of tissue sampling) before planned study inclusion, a new tumor biopsy before start of study treatment is mandatory. However, patients may be included in the trial with archival tissue not older than 3 months on the basis of a case by case discussion with the PI
Arm-specific Inclusion Criteria as determined by Whole Genome Sequencing and RNA Sequencing
in NCT/DKTK MASTER or identification by gene panel performed in a certified lab Eligibility
for the trial and the respective trial arms will be evaluated and determined exclusively by
the NCT/DKTK molecular tumor board on the basis of results from NCT/DKTK MASTER (for all
arms) or of results from other molecular studies, e.g. gene panel testing, performed in a
certified laboratory (for arms 1-6). Trial participation is only possible with a report of
the NCT/DKTK MASTER MTB confirming trial eligibility
Arm 1 (BRAF V600E/K): BRAF V600E/K mutation
Arm 2 (ERBB2): ERBB2 amplification/overexpression, activating ERBB2 mutation
Arm 3 (ALK): ALK rearrangement or activating ALK mutations including alternative
transcription initiation (ALK-ATI) or RET-fusions
Arm 4 (PI3K-AKT): Activating PIK3CA or AKT mutations; other aberrations predicting
increased PI3K-AKT pathway activity, e.g. PTEN loss in entities with no approval for
taxanes, i.e. nab-Paclitaxel, Paclitaxel or Docetaxel
Arm 5: (PI3K-AKT-TAX): Activating PIK3CA or AKT mutations; other aberrations
predicting increased PI3K-AKT pathway activity, e.g. PTEN loss in entities with
approval for taxanes, i.e. nab-Paclitaxel, Paclitaxel or Docetaxel
Arm 6 (MAPK): Aberrations other than BRAF V600E/K predicting increased RAF-MEK- ERK
pathway activity
Arm 7 (Immune evasion): High tumor mutational burden and/or specific alterations
predicting sensitivity to PD1/PDL1 inhibition (e.g. DNA mismatch repair deficiency or
PDL1 amplification and/or overexpression), ineligibility for the six specific arms

Exclusion Criteria

Clinical signs of active infection (>Grade 2 according to CTCAE version 5.0)
History of human immunodeficiency virus (HIV) infection and immunocompromised patients
Active Hepatitis A virus infection
Other malignancy except for study indication within the last 5 years except
Epilepsy requiring pharmacologic treatment
adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the
Pregnancy or breastfeeding
cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma, or
other malignancies curatively treated with no evidence of disease for ≥5 years
Major surgery within four weeks of starting study treatment
Concurrent or previous treatment within 30 days prior to C1D1 in another
interventional clinical trial with an investigational anticancer therapy
Heart failure New York Heart Association (NYHA) II/III/IV
Persistent toxicity (≥Grade 2 according to Common Terminology Criteria for Adverse
Severe obstructive or restrictive ventilation disorder
Events (CTCAE) version 5.0) caused by previous cancer therapy, excluding alopecia
Prior allogeneic bone marrow transplantation or solid organ transplant
Patients with clinical suspicion of active tuberculosis
Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B
surface antigen (HBsAg) test at baseline patients with a past or resolved HBV
Any concurrent antineoplastic therapy
infection, defined as having a negative HBsAg test and a positive total hepatitis B
Known suspected active alcohol or drug abuse
core antibody (HBcAb) test at baseline , are eligible for the study if active HBV
infection is ruled out on the basis of HBV DNA viral load per local guidelines
Evaluable or measurable disease outside the CNS
Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody
test at baseline confirmed by a polymerase chain reaction (PCR) positive for HCV RNA
No history of intracranial hemorrhage or spinal cord haemorrhage
Dementia or significant impairment of cognitive state
Inability to take oral medication orgastrointestinal disorders likely to interfere
with absorption of the study medication
Rash must cover less than 10% of body surface area (BSA)
Systemic chemotherapy or radiotherapy within two weeks prior to start of study
treatment or a longer period depending on the characteristics of the agents used (at
least five-half lives)
Administration of a live, attenuated vaccine within 4 weeks before initiation of study
treatment or anticipation that such a live attenuated vaccine will be required during
the study
Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates the use of an investigational drug
Is taking or requiring the continued use of any of the prohibited concomitant
medications listed in 5.10
Hematological malignancies and primary brain tumors. 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 symptomatic
uncontrolled brain metastases and patients with symptomatic uncontrolled spinal cord
compression 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 three months prior to enrollment
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
both prior to study enrolment. Patients with asymptomatic untreated CNS disease may be
enrolled, provided all of the following criteria are met
No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm
of the optic apparatus (optic nerves and chiasm)
No ongoing requirement for dexamethasone for CNS disease; patients on a stable
dose of anticonvulsants are permitted
Immune disease as specified below (relevant for all patients at Baseline except arm 3
(Alectinib))
History of autoimmune disease, including but not limited to myasthenia gravis
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid
arthritis, inflammatory bowel disease, vascular thrombosis associated with
antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome
Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
autoimmune-related hypothyroidism (patients on a stable dose of thyroid
replacement hormone are eligible for this study) and type I diabetes mellitus
(patients on a stable dose of insulin regimen are eligible for this study)
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g
bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or
active pneumonitis; history of radiation pneumonitis in the radiation field
(fibrosis) is permitted
Psoriatic arthritis (however, patients with eczema, psoriasis, lichen simplex
chronicus, or vitiligo with dermatologic manifestations only are permitted
provided that they meet the following conditions
Disease is well controlled at baseline and only requiring low potency topical
steroids
No acute exacerbations of underlying condition within the previous 12 months (not
requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids
biologic agents, oral calcineurin inhibitors, high potency or oral steroids])
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