Clinical trial NCT04029688: A Study Evaluating the Safety, Tolerability, Pharmacokinetics and Preliminary Activity of Idasanutlin in Combination With Either Chemotherapy or Venetoclax in Treatment of Pediatric and Young Adult Participants With Relapsed/Refractory Acute Leukemias or Solid Tumors
Official title: A Phase I/II, Multicenter, Open-Label, Multi-Arm Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Preliminary Activity of Idasanutlin in Combination With Either Chemotherapy or Venetoclax in the Treatment of Pediatric and Young Adult Patients With Relapsed/Refractory Acute Leukemias or Solid Tumors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia (AML)
Acute Lymphoblastic Leukemia (ALL)
Neuroblastoma
Solid Tumors
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2019-07-23
Enrollment: 38
Sex: ALL
Minimum age (years): 0
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This is a Phase I/II, multicenter, open-label, multi-arm study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of idasanutlin, administered as a single agent or in combination with chemotherapy or venetoclax, in pediatric and young adult participants with acute leukemias or solid tumors.

This study is divided into three parts: Part 1 will begin with dose escalation of idasanutlin as a single agent in pediatric participants with relapsed or refractory solid tumors to identify the maximum tolerated dose (MTD)/maximum administered dose (MAD) and to characterize dose-limiting toxicities (DLTs). Following MTD/MAD identification, three separate safety run-in cohorts in neuroblastoma, acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) will be conducted to identify the recommended Phase 2 dose (RP2D) of idasanutlin in each combination, with chemotherapy or venetoclax. Part 2 will evaluate the safety and early efficacy of idasanutlin in combination with chemotherapy or venetoclax in newly enrolled pediatric and young adult participants in neuroblastoma, AML,and ALL cohorts at idasanutlin RP2D. Part 3 will potentially be conducted as an additional expansion phase of the idasanutlin combination cohorts in neuroblastoma, AML, or ALL for further response and safety assessment.


Eligibility criteria: Inclusion Criteria:

* The participants ages are \< 18 for part 1a, \< 30 for Parts 1b. 2 and 3
* Study Part 1 (single-agent therapy dose escalation): histologically confirmed diagnosis of neuroblastoma or other solid tumor that has progressed or recurred despite standard therapy, and for which there is no therapy proven to prolong survival with an acceptable quality of life
* Study Part 1 (combination safety run-in), Study Part 2 (initial expansion), and Study Part 3 (additional expansion): histologically confirmed diagnosis of neuroblastoma, AML, or precursor-B ALL that has progressed or recurred despite, or is refractory to, standard therapy
* Adequate performance status: Participants \<16 years of age: Lansky greater than or equal to (≥)50%; Patients ≥16 years of age: Karnofsky ≥50%
* Adequate end-organ function, as defined in the protocol
* For females of childbearing potential: agreement to remain abstinent, use contraception, agreement to refrain from donating eggs. Females must remain abstinent or use two methods of contraception with a failure rate of \<1% per year during the treatment and follow-up period (variable depending on the combination agent) or in accordance with national prescribing information guidance regarding abstinence, contraception
* For males: agreement to remain abstinent or use a condom, and agreement to refrain from donating sperm, with a female partner of childbearing potential or pregnant female partner, males must remain abstinent or use a condom during the treatment period and for follow-up period (variable, depending on the combination agent) or in accordance with national prescribing information guidance regarding abstinence, contraception

Additional Inclusion Criteria for Participants with Solid Tumors (including Neuroblastoma)

* At least one evaluable or measurable radiological site of disease as defined by standard criteria for the participant's tumor type, or measurable bone marrow disease by morphology
* Adequate hematologic end-organ function, as defined in the protocol
* Tumor tissue from relapsed disease

Additional Inclusion Criteria for Patients with Leukemia

* Bone marrow with ≥5% lymphoblasts by morphologic assessment at screening
* Available bone marrow aspirate or biopsy from screening

Exclusion Criteria:

* Primary Central Nervous System (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
* Acute promyelocytic leukemia
* White blood cell count \>50 × 10\^9 cells/Liter (L)
* Down syndrome, Li-Fraumeni syndrome, history of severe aplastic anemia, or any known bone marrow failure predisposition syndrome
* Burkitt-type acute lymphoblastic leukemia
* T-cell lymphoblastic leukemia
* Prior treatment with a 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 participant
* Any uncontrolled medical condition or other identified abnormality that precludes the patient's safe participation in and completion of the study
* 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 for anti-neoplastic intent within 30 days prior to initiation of study treatment
* I-131 meta-iodobenzylguanidine (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 within 3 weeks prior to study treatment initiation
* Specific restrictions are applicable for patients treated with drugs interacting with CYP2C8, CYP3A4, OATP1B1/B3, and P-gp
* Received anti-coagulant or anti-platelet agent within 7 days or 5 half-lives prior to study treatment initiation
* Underwent major surgical procedure within 21 days of study treatment initiation, or anticipate need for major surgical procedure during the course of the study

Primary outcomes:
measure: Part 1a and 1b: Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE v5.0)
timeFrame: From screening up to 30 days after study treatment discontinuation (approximately 7 months)
measure: Parts 1a and 1b: Number of Participants With Dose-Limiting Toxicities (DLTs)
timeFrame: Cycle 1 (one cycle is 28 days)
measure: Part 1b: Objective Response Rate (ORR) in Participants With TP53 Wild-Type (WT) Neuroblastoma Assessed According to International Neuroblastoma Response Criteria (INRC)
timeFrame: From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
measure: Parts 2 and 3: ORR in Participants With TP53 WT Neuroblastoma Assessed According to INRC
timeFrame: Up to approximately 29 months
measure: Parts 2 and 3: Complete Remission Rate (CRR) in Participants With TP53 WT Leukemia
timeFrame: Up to Cycle 2 (cycle length=28 days) (approximately 8 weeks)
measure: Parts 2 and 3: Minimal Residual Disease (MRD) - Negative Rate in Participants With ALL
timeFrame: Up to Cycle 2 (cycle length=28 days) (approximately 8 weeks)
Secondary outcomes:
measure: Part 1a: Clinical Benefit Rate (CBR) in Participants With Solid Tumors From SE Population Assessed According to Response Evaluation Criteria Version 1.1 (RECIST v1.1) or INRC
timeFrame: From screening (maximum 28 days) up to Cycle 5 (cycle length=28 days)
measure: Part 1b: CBR in Participants With Neuroblastoma From SE Population Assessed According to INRC
timeFrame: From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
measure: Part 1b: CBR in Participants With TP53 WT Neuroblastoma Assessed According to INRC
timeFrame: From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
measure: Part 1a: Duration of Response (DOR) in Participants With Solid Tumors From SE Population Assessed According to RECIST v1.1 or INRC
timeFrame: From screening (maximum 28 days) up to Cycle 5 (cycle length=28 days)
measure: Part 1b: DOR in Participants With Neuroblastoma From SE Population Assessed According to INRC
timeFrame: From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
measure: Part 1b: DOR in in Participants With TP53 WT Neuroblastoma Assessed According to INRC
timeFrame: From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
measure: Part 1a: Progression Free Survival (PFS) in Participants With Solid Tumors From SE Population Assessed According to RECIST v1.1 or INRC
timeFrame: From screening (maximum 28 days) up to Cycle 5 (cycle length=28 days)
measure: Part 1b: PFS in Participants With Neuroblastoma From SE Population Assessed According to INRC
timeFrame: From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
measure: Part 1b: PFS in Participants With TP53 WT Neuroblastoma Assessed According to INRC
timeFrame: From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
measure: Parts 1a and 1b: Overall Survival (OS) in SE Population
timeFrame: Up to approximately 29 months
measure: Part 1b: OS in Participants With TP53 WT Neuroblastoma
timeFrame: Up to approximately 29 months
measure: Part 1a: ORR Irrespective of TP53 Status in Participants With Solid Tumor From SE Population According to RECIST v1.1 or INRC
timeFrame: From screening (maximum 28 days) up to Cycle 5 (cycle length=28 days)
measure: Part 1b: ORR Irrespective of TP53 Status in Participants With Neuroblastoma From SE Population According to INRC
timeFrame: From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)
measure: Part 1a: Maximum Plasma Concentration (Cmax) of Idasanutlin as a Monotherapy
timeFrame: Days 1 and 5 of Cycle 1 (cycle length = 28 days)
measure: Part 1b: Cmax of Idasanutlin in Combination With Chemotherapy or Venetoclax
timeFrame: Days 1 and 5 of Cycle 1 (cycle length = 28 days)
measure: Part 1a: Cmax of Idasanutilin Metabolite M4 Following Idasanutilin as a Monotherapy
timeFrame: Days 1 and 5 of Cycle 1 (cycle length = 28 days)
measure: Part 1b: Cmax of Idasanutlin Metabolite M4 (Idasanutilin in Combination With Chemotherapy or Venetoclax)
timeFrame: Days 1 and 5 of Cycle 1 (cycle length = 28 days)
measure: Part 1b: Plasma Concentration of Venetoclax in Combination With Idasanutlin
timeFrame: Cycle 1: Predose on Days 2 and 5, 4 and 6 hours post dose on Days 1 and 5 (1 cycle = 28 days)
measure: Parts 1, 2 and 3: Number of Participants With Leukemia Receiving Transplant After Study Treatment
timeFrame: Up to approximately 29 months
measure: Parts 1, 2 and 3: Duration of Objective Response in Participants With Leukemia
timeFrame: Up to approximately 29 months
measure: Parts 1, 2 and 3: Event-Free Survival (EFS) in Participants With Leukemia
timeFrame: Up to approximately 29 months
measure: Parts 1, 2 and 3: OS in Participants With Leukemia
timeFrame: Up to approximately 29 months
measure: Parts 1, 2 and 3: CRR of Efficacy-evaluable Population Irrespective of TP53 Status in Participants With Leukemia
timeFrame: Up to approximately 29 months
measure: Parts 1, 2 and 3: MRD - Negative Rate in Participants With ALL
timeFrame: Up to approximately 29 months
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Children's Hospital Research Institute
state: Arkansas
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital at Stanford University; Thoracic Oncology
state: California
city: Orlando
country: United States
facility: Arnold Palmer Hosp-Children
state: Florida
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Calgary
country: Canada
facility: Alberta Children'S Hospital
state: Alberta
city: Lyon CEDEX 08
country: France
facility: Centre Leon Berard
city: Paris
country: France
facility: Institut Curie
city: Utrecht
country: Netherlands
facility: Prinses Maxima Centrum
city: Esplugues De Llobregas
country: Spain
facility: Hospital Sant Joan De Deu
state: Barcelona
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Nino Jesus
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
city: Newcastle Upon Tyne
country: United Kingdom
facility: The Royal Victoria Infirmary; Paediatric and Adolescent Oncology Unit
city: Surrey
country: United Kingdom
facility: Royal Marsden Hospital; Pediatric Unit
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: