Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Navitoclax · 7 trials · 14 indications
Reduction in spleen volume is measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT), per International Working Group (IWG) criteria.
The investigators will monitor each subject for clinical and lab evidence of adverse events on a routine basis through out the study. The investigators will question each subject regarding any adverse effects that they have experienced and record any events on the care report forms. All adverse events will be followed to a satisfactory clinical resolution.
Physical exam, blood pressure, pulse, body temperature will be measured and recorded
Chemistry, hematology, urinalysis lab tests will be measured and recorded. All clinically significant values will be followed by the investigator to a satisfactory clinical resolution.
The Bayesian optimal interval (BOIN) design will be employed to find the MTD. The BOIN design is implemented in a simple way. It is more flexible and possesses superior operating characteristics that are comparable to those of the more complex model based designs.
A 90% confidence interval will be computed for the CR rate by cycle 4.
The RP2D is the minimally safe and biologically effective dose. The minimally safe dose is the highest dose level at which \<2 of 6 participants experience a dose limiting toxicity (DLT). See subsequent primary outcome for the DLT definition. With respect to safety, the RP2D will also consider laboratory evidence of platelet recovery. Evaluation of efficacy will be done in real time prioritizing full complete response (see subsequent secondary outcome for the objective response criteria) when possible for AML/MDS/MDS-MPN and transfusion independence/blast reduction/TSS improvement/splenic reduction for myelofibrosis.
DLT is defined by hematologic or non-hematologic adverse event (AE) per protocol (section 5.4); A treatment-related death is a DLT; AEs are graded based on NCI CTCAE v5.0 and must be considered unrelated to the underlying disease or co-morbidity to be a DLT.
Dose limiting toxicities for dose escalation purposes will be determined on events that occur during the first 28-day cycle of navitoclax.
Maximum Observed Plasma Concentration (Cmax) of Navitoclax.
Maximum Observed Plasma Concentration (Cmax) of Celecoxib.
Tmax defined as time to maximum observed plasma concentration of Navitoclax.
Tmax defined as time to maximum observed plasma concentration of Celecoxib.
Area under the plasma concentration-time curve from time zero to the last measurable concentration of Navitoclax.
Area under the plasma concentration-time curve from time zero to the last measurable concentration of Celecoxib.
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.
Change in QTcF (Part 3).
Maximum observed plasma concentration (Cmax) of venetoclax + navitoclax
Area under the plasma concentration-time curve (AUC) of venetoclax + navitoclax
Time to Cmax (Tmax) of Venetoclax + Navitoclax
Apparent oral clearance (CL/F) of venetoclax + navitoclax
A DLT is any Grade 3 or higher non-hematologic adverse event (AE) with exceptions outlined in the protocol. AEs and toxicities that occur beyond the DLT assessment period will also be evaluated by the investigator and AbbVie and may be considered as dose-limiting.
| Arm | Type | Description |
|---|---|---|
| Arm A: Navitoclax + Ruxolitinib | EXPERIMENTAL | Participants will receive navitoclax tablets once daily and ruxolitinib tablets twice daily. |
| Arm B: Best Available Therapy (BAT) | ACTIVE_COMPARATOR | Participants will receive one of the BAT options, per the investigator's discretion. |
| Arm C: Continued Access for Navitoclax | EXPERIMENTAL | Participants will receive navitoclax tablets once daily. |
| Navitoclax, ABT-263 | EXPERIMENTAL | - |
| Treatment (navitoclax, decitabine, venetoclax) | EXPERIMENTAL | This is a single-center trial of navitoclax, venetoclax and decitabine in adult patients with R/R HR-MDS who have previously failed HMA therapy. This trial was intended to be a Phase 1/2 trial but the trial never moved forward to Phase 2. In the phase I dose escalation portion, patients will receive navitoclax in combination with standard dosing of venetoclax and decitabine. The maximally tolerated dose (MTD) will be the recommended phase II dose (RP2D). Previously, navitoclax in combination with venetoclax and chemotherapy in ALL found the MTD to 50mg of nativoclax po. In the phase II dose expansion portion, patients will receive navitoclax at the RP2D in combination with standard dose venetoclax and decitabine. Patients will continue on treatment with navitoclax, venetoclax and decitabine until relapse, dose-limiting toxicity, availability of alternate therapy or withdrawal of consent. |
| Dose Level 0: Decitabine + Venetoclax + Navitoclax [AML and Non-AML] | EXPERIMENTAL | Dose Level 0 \[AML and Non-AML\] Decitabine \[intravenously (IV) preferred\] Venetoclax Cycle 1: ramp-up days 1-2 and days 3-14 absence of strong/moderate CYP3A inhibitor and reduced doses dependent on presence of moderate or strong CYP3A inhibitor Cycle 2+: dosing days 1-14 Navitoclax Cycle 1: dosing days 3-14; Cycle 2+: dosing on days 1-14 Cycle length=28 days Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons. |
| Dose Level 1: Venetoclax + Decitabine + Navitoclax [AML and Non-AML] | EXPERIMENTAL | Dose Level 1 \[AML and Non-AML\] Decitabine \[intravenously (IV) preferred\] Cycle 1+: dosing on days 1-5 Venetoclax \[orally\] Cycle 1: ramp-up starting on day 1-2 then days 3-14 continued dosing in absence of strong/moderate CYP3A inhibitor and reduced doses dependent on presence of moderate or strong CYP3A inhibitor Cycle 2+: dosing days 1-14 Navitoclax \[orally\] Cycle 1: Dosing days 3-14 Cycle 2+: dosing on days 1-14 Cycle length=28 days Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons. |
| Dose Level 2: Venetoclax + Decitabine + Navitoclax [AML] | EXPERIMENTAL | Dose Level 2 \[AML\] Decitabine \[intravenously (IV) preferred\] Cycle 1+: dosing on days 1-5 Venetoclax \[orally\] Cycle 1: ramp-up on day 1-2, days 3-21 continued dosing in absence of strong/moderate CYP3A inhibitor and reduced doses dependent on presence of moderate or strong CYP3A inhibitor Cycle 2+: dosing on days 1-21 Navitoclax \[orally\] Cycle 1: dosing on days 3-14 Cycle 2+: dosing on days 1-14 Cycle length=28 days Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons. |
| Dose Level -1: Venetoclax + Decitabine + Navitoclax [Non-AML] | EXPERIMENTAL | Dose Level -1 \[Non-AML\] Decitabine \[intravenously (IV) preferred\] Cycle 1+:dosing \[intravenously (IV) preferred\] on days 1-3 Venetoclax \[orally\] Cycle 1: ramp-up of starting day 1-2 then days 3-7 continued dosing in absence of strong/moderate CYP3A inhibitor and reduced doses dependent on presence of moderate or strong CYP3A inhibitor Cycle 2+: dosing on days 1-7 Navitoclax \[orally\] Cycle 1: Dosing days 3-14 Cycle 2+: continued dosing on days 1-14 Cycle length=28 days Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons. |
| Recommended Phase 2 Dose Level: Venetoclax + Decitabine + Navitoclax [AML and Non-AML] | EXPERIMENTAL | RP2D \[AML and Non-AML\] Decitabine \[intravenously (IV) preferred\] To be determined based on dose escalation design. Venetoclax \[orally\] To be determined based on dose escalation design. Navitoclax \[orally\] To be determined based on dose escalation design. Cycle length=28 days Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons. |
| Part 1: Navitoclax Monotherapy | EXPERIMENTAL | Participants will receive various doses of navitoclax once daily (QD). |
| Part 2: Navitoclax + Ruxolitinib Combination Therapy | EXPERIMENTAL | Participants will receive various doses of navitoclax once daily (QD) in combination with ruxolitinib twice daily (BID). |
| Part 3: Navitoclax Monotherapy | EXPERIMENTAL | Participants will receive navitoclax once daily (QD). |
| Part 4: Navitoclax + Celecoxib | EXPERIMENTAL | Participants will receive navitoclax once daily (QD) starting on Day 3. Participants will also receive celecoxib single dose on Day 1 and Day 7. |
| Part 5: Navitoclax + Ruxolitinib Combination Therapy | EXPERIMENTAL | Participants will receive ruxolitinib BID and navitoclax QD for drug-drug interaction (DDI) assessment, followed by continued administration of navitoclax in combination with ruxolitinib. |
| Venetoclax + Navitoclax + Chemotherapy | EXPERIMENTAL | Venetoclax weight-adjusted doses administered orally every day (QD) starting on Day 1 + navitoclax various, weight-adjusted doses administered orally QD starting on Day 3 + chemotherapy (peg-asparaginase \[or any other forms of asparaginase\], vincristine, dexamethasone) and tyrosine kinase inhibitor \[TKI, if applicable\]). This regimen and any of its components may be delayed, reduced or omitted at the discretion of the Investigator. |
| Arm A (navitoclax and rifampin) | EXPERIMENTAL | - |
| Name | Type | Description |
|---|---|---|
| Navitoclax | DRUG | Tablet; Oral |
| Ruxolitinib | DRUG | Tablet; Oral |
| Best Available Therapy (BAT) | DRUG | Tablet/Capsule; Oral or Solution for Subcutaneous Injection |
| Venetoclax | DRUG | Given PO |
| Decitabine | DRUG | Given IV |
| Bone Marrow Biopsy | PROCEDURE | Undergo bone marrow biopsy |
| Biospecimen Collection | PROCEDURE | Undergo collection of blood |
| Laboratory Biomarker Analysis | OTHER | Correlative studies |
| Quality-of-Life Assessment | OTHER | Ancillary studies |
| Celecoxib | DRUG | Capsule; Oral |
| Chemotherapy | DRUG | peg-asparaginase (or other form of asparaginase, per local standard of care (intravenous) + vincristine (intravenous) + dexamethasone (oral) + tyrosine kinase inhibitor (TKI) (if applicable, oral) |
| Rifampin | DRUG | Subjects will be dosed with Navitoclax, then, dosed with Navitoclax in combination with Rifampin. |
Inclusion Criteria: * Must complete the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 on at least 4 out of the 7 days immediately prior to the date of randomization and must agree to collect MFSAF data daily by ePRO device during the study collection window. \-- Has at least 2 symptoms each...