Solid Tumors / Neuroblastoma Bloodcancer solid tumors
Conditions
Interventions
The investigational medicinal products (IMPs) for this study are idasanutlin,
venetoclax, cyclophosphamide, topotecan, fludarabine, and cytarabine.
Test Product (Investigational Drug)
Idasanutlin wi
300 mg equivalent Day 2
600
mg equivalent Day 3). If lower doses of venetoclax are required, intermediate
doses for the ramp up will be proportionally adapted ba
Sponsors
Hoffmann-La Roche
Eligibility
Age
2 Years to 64 Years
Inclusion criteria
Inclusion criteria: Signed informed consent before any study-specific screening procedures are conducted, and age-appropriate assent when considered appropriate according to local, regional, or national guidelines Age
Exclusion criteria
Exclusion criteria: Primary CNS tumors Symptomatic CNS metastases that result in a neurologically unstable clinical state or require increasing doses of corticosteroids or local CNS-directed therapy to control the CNS disease CNS3 leukemia (total nucleated cell count at least 5/*L with blasts on cytocentrifuge in an atraumatic lumbar puncture, or clinical signs of CNS leukemia including cranial nerve palsy) Acute promyelocytic leukemia White blood cell count more than 50 * 109/L Down syndrome, Li-Fraumeni syndrome, history of severe aplastic anemia, or any known bone marrow failure predisposition syndrome (including, but not limited to, Fanconi anemia or dyskeratosis congenita) Burkitt-type acute lymphoblastic leukemia (mature B-cell) T-cell lymphoblastic leukemia Prior treatment with an MDM2 antagonist Prior treatment with venetoclax (if potential for enrollment in a venetoclax arm) Infection considered by the investigator to be clinically uncontrolled or of unacceptable risk to the patient upon induction of neutropenia, including patients who are, or should be, on antimicrobial agents for the treatment of active infection. Pregnant or breastfeeding, or intending to become pregnant during the study Females of childbearing potential must have a negative serum pregnancy test result within 1 week prior to initiation of study drug. Active GI disease (e.g., gut graft-versus-host disease, Crohn's disease, ulcerative colitis) or GI conditions that may significantly alter drug absorption of oral drugs (e.g., uncontrolled vomiting, diarrhea, or malabsorption syndrome) Active viral hepatitis or human immunodeficiency virus (HIV) infection Presence of any CTCAE at least Grade 2 clinically significant treatment-related toxicity with the exception of alopecia, ototoxicity, peripheral neuropathy and parameters otherwise permitted in the inclusion criteria (e.g., hematological criteria) Clinically relevant QTc prolongation (QTcF more than 450 ms using the Fridericia correction) Any uncontrolled medical condition or other identified abnormality that precludes the patient's safe participation in and completion of the study, as judged by the investigator Systemic anticancer therapy within 28 days or 5 half-lives, whichever is shorter, prior to initiation of study treatment Treatment with monoclonal antibodies, antibody drug conjugates, or cellular therapy (e.g., CAR-T cell infusion) for anti-neoplastic intent within 30 days prior to initiation of study treatment I-131 MIBG therapy within 6 weeks prior to initiation of study treatment Myeloablative therapy with autologous or allogeneic hematopoietic stem cell rescue within 100 days of study treatment initiation Immunosuppressive therapy for treatment of graft-versus-host disease within 2 weeks of study treatment initiation Radiotherapy (non-palliative) within 3 weeks prior to study treatment initiation Known hypersensitivity to any study drug or component of the formulation that could potentially be allocated according to tumor type Received the following within 7 days prior to initiation of study treatment: - Strong CYP2C8 inhibitors - CYP2C8 substrates - OATP1B1/3 substrates Received strong CYP2C8 and strong CYP3A4 inducers within 14 days prior to the initiation of study treatment For patients assigned or randomi
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The primary efficacy objective for this study (Study Parts 1b, 2 and 3) is to evaluate the anti cancer activity of idasanutlin in combination with chemotherapy or venetoclax on the basis of the following endpoints: Neuroblastoma - Objective response rate (ORR), defined as the proportion of patients with complete response or partial response (PR) at any time during study treatment, on two consecutive occasions more or equal to 4 weeks apart, as determined by the investigator according to INRC for patients with neuroblastoma. Primary efficacy analysis will be conducted on patients with TP53 wild-type (WT) tumors in Study Parts 1b, 2 and 3. Leukemia - Complete remission rate (CRR), defined as the proportion of patients with morphologic complete remission, complete remission with incomplete blood count recovery (CRi) or complete remission with incomplete platelet count recovery (CRp), within 2 cycles of study treatment - For patients with acute lymphocytic leukemia (ALL): minimal residual disease (MRD)-negative rate, defined as the proportion of patients with ALL who have an MRD value | — |
Secondary
| Measure | Time frame |
|---|---|
| The secondary efficacy objective for this study (Study Parts 1, 2, and 3) is to evaluate the anti cancer activity of idasanutlin as single agent, in combination with chemotherapy, and in combination with venetoclax (in patients with TP53 WT tumors, as well as in all patients regardless of mutation status) on the basis of the following endpoints: Solid tumors (including Neuroblastoma) - Clinical benefit rate (CBR), defined as the proportion of patients achieving confirmed complete response, PR, or SD on two consecutive occasions more or equal to 4 weeks apart during the total study period - Duration of objective response (DOR), defined as the time from the first tumor assessment that supports a patient*s objective response to the time of disease progression or death from any cause (whichever occurs first), as determined by the investigator using INRC for patients with neuroblastoma or RECIST v1.1 for patients with other solid tumors - Progression-free survival (PFS), defined as the time from initiation of study drug to the first documented occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator using INRC for patients with neuroblastoma and RECIST v1.1 for patients with other solid tumors - Overall survival (OS), defined as the time from initiation of study drug to death from any cause - ORR of efficacy-evaluable population irrespective of TP53 mutation status Leukemia - Number of patients receiving transplant after study treatment - DOR, defined as the time from the first tumor assessment that supports the patient's objective response (CR, CRp, CRi) to the time of relapse, or death from any cause, whichever occurs first - EFS, defined as the time from initiation of study drug to the first documented occurrence of M3 marrow after Cycle 1, failure to achieve CR/CRp/CRi after Cycle 2, disease progression, relapse subsequent to achieving CR/CRp/CRi, or death from any cause, which | — |
Countries
Netherlands
Outcome results
None listed