Phase 1/2 Study of ABI-009 in Nonmuscle Invasive Bladder Cancer

Study Overview
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Brief Summary
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Purpose of this study is to determine appropriate dosing of ABI-009 and evaluate the safety and anti-tumor activity of ABI-009 in treatment of non-muscle invasive bladder cancer

Official Title
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A Combined Phase 1 and Phase 2 Study of Albumin-bound Rapamycin Nanoparticles (Nab-rapamycin, ABI-009) in the Treatment of BCG Refractory or Recurrent Nonmuscle Invasive Transitional Cell Bladder Cancer

Conditions
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Non-muscle Invasive Bladder Cancer (NMIBC)

Intervention / Treatment
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* Drug: ABI-009
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a diagnosis of transitional cell carcinoma (TCC) of the urinary bladder confirmed at the study institution. The patient must have demonstrated nonmuscle-invasive bladder cancer refractory or recurrent to standard intravesical therapy. Refractory disease is defined as failure to achieve tumor-free status by 6 months of initiation of adequate BCG therapy. Recurrent disease is defined as reappearance of disease after achieving a tumor-free status by 6 months of initiation of adequate BCG therapy. Adequate BCG therapy includes at least 6 weeks induction plus 3 additional doses of either induction or maintenance. Patients with a history of other intravesical agents (except nab-rapamycin or gemcitabine) in addition to standard BCG will also be allowed to enroll. All grossly visible disease must be fully resected and pathologic stage will be confirmed at the institution where the patient is enrolled. This will include stage Ta, T1, Tis and exclude all patients with muscle invasion (T2). For phase 1, patients with multifocal low-grade Ta histology will be eligible for participation For phase 2, individuals with Ta disease only must have documentation of high-grade histology For phase 2, prior intravesical treatment with nab-rapamycin or gemcitabine is not allowed Age >18 and must be able to read, understand, and sign informed consent Performance Status: ECOG 0, 1, and 2 (See Appendix III) Hematologic inclusion within 2 weeks of start of treatment Absolute neutrophil count >1,500/mm3 Hemoglobin >9.0 g/dl Platelet count >100,000/mm3 Hepatic inclusion within 2 weeks of entry Total bilirubin must be within normal limits. Adequate renal function with serum creatinine ≤2.5 mg/dL Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 x ULN for the institution, alkaline phosphatase ≤ 2.5 x ULN for the institution, unless bone metastasis is present in the absence of liver metastasis Women of childbearing potential must have a negative pregnancy test. All patients of childbearing potential must be willing to consent to using effective contraception, ie, intrauterine device, birth control pills, depo-provera, and condoms while on treatment and for 3 months after their participation in the study ends. Exclusion Criteria: Any other malignancy diagnosed within 1 year of study entry (except basal or squamous cell skin cancers or noninvasive cancer of the cervix) is excluded Concurrent treatment with any chemotherapeutic agent Women who are pregnant or lactating History of vesicoureteral reflux or an indwelling urinary stent Participation in any other research protocol involving administration of an investigational agent within 1 month prior to study entry History of radiation to the pelvis History of interstitial lung disease and/or pneumonitis Evidence of metastatic disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The phase 1 dose-escalation portion used the 3+3 dose escalation rule. Initially 3 patients will be treated. If none develops DLT following the third weekly instillation, the dose can be escalated. If only 1 of the first 3 patients develops DLT, then an additional 3 patients will be treated at that dose. At any dose level, if 2 or more cases develop DLT, the prior dose will be defined as the MDD once 6 patients have been treated at this level with less than 2 patients experiencing a DLT. In phase 2, up to 29 patients will receive intravesical ABI-009 and gemcitabine using the Simon 2-stage design: initially, there will be only 10 patients enrolled with a rejection rule that only if there are 2 or more positive responses will the study proceed to further enrollment of the next 19 patients.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: ABI-009 100 mg/week<br>Phase 1, Cohort 1: ABI-009 injectable suspension, 100 mg in 80 mL 0.9% saline, administered intravesically and retained for 2 hours, once per week for 6 weeks | Drug: ABI-009<br>* ABI-009 is a nanoparticle albumin-bound (nab®) formulation of the mammalian Target of Rapamycin ( mTOR) inhibitor, sirolimus. Specifically, ABI-009 is a sterile lyophilized powder of albumin-bound sirolimus nanoparticles with a mean particle size of less than 100 nm.<br>* Other names: nab-rapamycin;|
| Experimental: Phase 1: ABI-009 200 mg/week<br>Phase 1, Cohort 2: ABI-009 injectable suspension, 200 mg in 80 mL 0.9% saline, administered intravesically and retained for 2 hours, once per week for 6 weeks | Drug: ABI-009<br>* ABI-009 is a nanoparticle albumin-bound (nab®) formulation of the mammalian Target of Rapamycin ( mTOR) inhibitor, sirolimus. Specifically, ABI-009 is a sterile lyophilized powder of albumin-bound sirolimus nanoparticles with a mean particle size of less than 100 nm.<br>* Other names: nab-rapamycin;|
| Experimental: Phase 1: ABI-009 100 mg 2×/week<br>Phase 1, Cohort 2b: ABI-009 injectable suspension, 100 mg in 80 mL 0.9% saline, administered intravesically and retained for 2 hours, twice per week (total dose 200 mg per week) for 6 weeks | Drug: ABI-009<br>* ABI-009 is a nanoparticle albumin-bound (nab®) formulation of the mammalian Target of Rapamycin ( mTOR) inhibitor, sirolimus. Specifically, ABI-009 is a sterile lyophilized powder of albumin-bound sirolimus nanoparticles with a mean particle size of less than 100 nm.<br>* Other names: nab-rapamycin;|
| Experimental: Phase 1: ABI-009 300 mg/week<br>Phase 1, Cohort 3: ABI-009 injectable suspension, 300 mg in 80 mL 0.9% saline, administered intravesically and retained for 2 hours, once per week for 6 weeks | Drug: ABI-009<br>* ABI-009 is a nanoparticle albumin-bound (nab®) formulation of the mammalian Target of Rapamycin ( mTOR) inhibitor, sirolimus. Specifically, ABI-009 is a sterile lyophilized powder of albumin-bound sirolimus nanoparticles with a mean particle size of less than 100 nm.<br>* Other names: nab-rapamycin;|
| Experimental: Phase 1: ABI-009 400 mg/week<br>Phase 1, Cohort 4: ABI-009 injectable suspension, 400 mg in 80 mL 0.9% saline, administered intravesically and retained for 2 hours, once per week for 6 weeks | Drug: ABI-009<br>* ABI-009 is a nanoparticle albumin-bound (nab®) formulation of the mammalian Target of Rapamycin ( mTOR) inhibitor, sirolimus. Specifically, ABI-009 is a sterile lyophilized powder of albumin-bound sirolimus nanoparticles with a mean particle size of less than 100 nm.<br>* Other names: nab-rapamycin;|
| Experimental: Phase 2: ABI-009 400 mg/week + Gemcitabine 2000 mg/week<br>ABI-009 injectable suspension, 200 mg in 80 mL 0.9% saline, administered intravesically and retained for 1 hour, once per week for 6 weeks; Gemcitabine, 2000 mg in 100 mL saline, administered intravesically after voiding of ABI-009 and retained for 1 hour, once per week for 6 weeks | Drug: ABI-009<br>* ABI-009 is a nanoparticle albumin-bound (nab®) formulation of the mammalian Target of Rapamycin ( mTOR) inhibitor, sirolimus. Specifically, ABI-009 is a sterile lyophilized powder of albumin-bound sirolimus nanoparticles with a mean particle size of less than 100 nm.<br>* Other names: nab-rapamycin;Drug: Gemcitabine<br>* Gemcitabine is administered after ABI-009 in the Phase 2 study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Dose Limiting Toxicities (DLT) Following Intravesical Administration of ABI-009 | The primary endpoint of the Phase 1 study is DLT following intravesical administration of ABI-009 in patients with BCG refractory or recurrent nonmuscle-invasive transitional cell carcinoma (TCC) of the bladder to identify maximum deliverable dose (MDD). Systemic DLT will be defined as any grade systemic toxicity using the NCI CTCAE version 4.0. Local dose limiting toxicity was defined as grade 3 or 4 bladder toxicity (hematuria, dysuria, urinary retention, urinary frequency/urgency, or bladder spasms) using the NCI CTCAE version 4.0. | Duration of treatment (6 weeks) plus 30 days follow up (up to 2.5 months) | 
| Phase 2: Number of Participants Achieving a Complete Response Following Intravesical Administration of ABI-009 and Gemcitabine | The primary objective of the Phase 2 study is to evaluate the utility (potential for clinical efficacy) of ABI-009 in combination with gemcitabine in the treatment of BCG refractory or recurrent nonmuscle-invasive TCC of the bladder. Response rate will be measured and documented at the 6-week post-treatment assessment, including cystoscopy with biopsy. A complete response is defined as a cancer-negative biopsy at the 6-week post-treatment cystoscopy. No response will be defined as positive cystoscopic biopsy. | End of Study [EOS, 3 months] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number of Participants Achieving a Complete Response Following Intravesical Administration of ABI-009 | Response rate will be measured and documented at the 6-week post-treatment assessment, including cystoscopy with biopsy. A complete response is defined as a cancer-negative biopsy at the 6-week post-treatment cystoscopy. No response will be defined as positive cystoscopic biopsy. | End of Study [EOS, 3 months] |