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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02009332
Recruitment Status : Completed
First Posted : December 12, 2013
Results First Posted : June 8, 2021
Last Update Posted : June 8, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Aadi, LLC

Brief Summary:
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

Condition or disease Intervention/treatment Phase
Non-muscle Invasive Bladder Cancer (NMIBC) Drug: ABI-009 Drug: Gemcitabine Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : April 9, 2014
Actual Primary Completion Date : December 1, 2019
Actual Study Completion Date : December 1, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer

Arm Intervention/treatment
Experimental: Phase 1: ABI-009 100 mg/week
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
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.
Other Names:
  • nab-sirolimus
  • nab-rapamycin

Experimental: Phase 1: ABI-009 200 mg/week
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
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.
Other Names:
  • nab-sirolimus
  • nab-rapamycin

Experimental: Phase 1: ABI-009 100 mg 2×/week
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
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.
Other Names:
  • nab-sirolimus
  • nab-rapamycin

Experimental: Phase 1: ABI-009 300 mg/week
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
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.
Other Names:
  • nab-sirolimus
  • nab-rapamycin

Experimental: Phase 1: ABI-009 400 mg/week
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
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.
Other Names:
  • nab-sirolimus
  • nab-rapamycin

Experimental: Phase 2: ABI-009 400 mg/week + Gemcitabine 2000 mg/week
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
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.
Other Names:
  • nab-sirolimus
  • nab-rapamycin

Drug: Gemcitabine
Gemcitabine is administered after ABI-009 in the Phase 2 study.




Primary Outcome Measures :
  1. Phase 1: Dose Limiting Toxicities (DLT) Following Intravesical Administration of ABI-009 [ Time Frame: Duration of treatment (6 weeks) plus 30 days follow up (up to 2.5 months) ]
    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.

  2. Phase 2: Number of Participants Achieving a Complete Response Following Intravesical Administration of ABI-009 and Gemcitabine [ Time Frame: End of Study [EOS, 3 months] ]
    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.


Secondary Outcome Measures :
  1. Phase 1: Number of Participants Achieving a Complete Response Following Intravesical Administration of ABI-009 [ Time Frame: End of Study [EOS, 3 months] ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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).

    1. For phase 1, patients with multifocal low-grade Ta histology will be eligible for participation
    2. For phase 2, individuals with Ta disease only must have documentation of high-grade histology
    3. For phase 2, prior intravesical treatment with nab-rapamycin or gemcitabine is not allowed
  2. Age >18 and must be able to read, understand, and sign informed consent
  3. Performance Status: ECOG 0, 1, and 2 (See Appendix III)
  4. Hematologic inclusion within 2 weeks of start of treatment

    1. Absolute neutrophil count >1,500/mm3
    2. Hemoglobin >9.0 g/dl
    3. Platelet count >100,000/mm3
  5. Hepatic inclusion within 2 weeks of entry

    1. Total bilirubin must be within normal limits.
    2. Adequate renal function with serum creatinine ≤2.5 mg/dL
    3. 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
  6. Women of childbearing potential must have a negative pregnancy test.
  7. 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:

  1. 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
  2. Concurrent treatment with any chemotherapeutic agent
  3. Women who are pregnant or lactating
  4. History of vesicoureteral reflux or an indwelling urinary stent
  5. Participation in any other research protocol involving administration of an investigational agent within 1 month prior to study entry
  6. History of radiation to the pelvis
  7. History of interstitial lung disease and/or pneumonitis
  8. Evidence of metastatic disease

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02009332


Locations
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United States, New York
Columbia University Medical Center
New York, New York, United States, 10032
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Aadi, LLC
National Cancer Institute (NCI)
Investigators
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Principal Investigator: James McKiernan, MD Columbia University
  Study Documents (Full-Text)

Documents provided by Aadi, LLC:
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Responsible Party: Aadi, LLC
ClinicalTrials.gov Identifier: NCT02009332    
Other Study ID Numbers: BC001
1R42CA171552-01 ( U.S. NIH Grant/Contract )
First Posted: December 12, 2013    Key Record Dates
Results First Posted: June 8, 2021
Last Update Posted: June 8, 2021
Last Verified: May 2021
Additional relevant MeSH terms:
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Urinary Bladder Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Gemcitabine
Sirolimus
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Antibiotics, Antineoplastic
Antifungal Agents