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Recurrent MelanomaPhase 1/2NCT01196416

Gamma-secretase/Notch Signalling Pathway Inhibitor RO4929097 in Combination With Cisplatin, Vinblastine, and Temozolomide in Treating Patients With Recurrent or Metastatic Melanoma

A Phase 1/2 study testing Cisplatin, Gamma-Secretase Inhibitor RO4929097 and Laboratory Biomarker Analysis in people with Recurrent Melanoma and Stage IV Skin Melanoma, run by National Cancer Institute (NCI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This phase Ib/II trial studies the side effects and best dose of gamma-secretase/Notch signalling pathway inhibitor RO4929097 when given together with cisplatin, vinblastine, and temozolomide and to see how well they work in treating patients with recurrent or metastatic melanoma. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Recurrent Melanoma, Stage IV Skin Melanoma
What is being tested?
Cisplatin, Gamma-Secretase Inhibitor RO4929097 and Laboratory Biomarker Analysis
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
14 participants
Where
1 siteUnited States
Study dates
Aug 2010to Aug 2015
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients must have histologically or cytologically Memorial Sloan Kettering Cancer Center (MSKCC) confirmed recurrent or metastatic melanoma
  • All Patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be > 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or > 20 mm when measured by chest x-ray; lymph nodes must be > 15 mm in short axis when measured by CT or MRI
  • Patients may have had up to one prior systemic therapy for recurrent or metastatic disease, but cannot have previously been treated with cisplatin, vinblastine, temozolomide, dacarbazine, or a gamma-secretase inhibitor; at least 3 weeks must have elapsed since the last dose of systemic therapy; for small molecule targeted therapy, at least 5 half-lives must have elapsed; at least 6 weeks must have elapsed if the last regimen included carmustine (BCNU) or mitomycin C or an anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) antibody
  • Life expectancy of greater than 3 months
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Hemoglobin >= 9 g/dL
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  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< institutional upper limit of normal
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 X institutional upper limit of normal
  • Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Women of childbearing potential and men must use two forms of contraception (i.e., barrier contraception and one other method of contraception) at least 4 weeks prior to study entry, for the duration of study participation, and for at least 12 months post-treatment; should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study and for 12 months after study participation, the patient should inform the treating physician immediately
  • Women of childbearing potential are required to have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 10-14 days and within 24 hours prior to the first dose of RO4929097 (serum or urine); a pregnancy test (serum or urine) will be administered every 4 weeks if their menstrual cycles are regular or every 2 weeks if their cycles are irregular while on study within the 24-hour period prior to the administration of RO4929097; a positive urine test must be confirmed by a serum pregnancy test; prior to dispensing RO4929097, the investigator must confirm and document the patient's use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of the teratogenic potential of RO4929097
  • Female patients of childbearing potential are defined as follows:
  • Patients with regular menses
  • Patients, after menarche with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding
  • Women who have had tubal ligation
  • Female patients may be considered to NOT be of childbearing potential for the following reasons:
  • The patient has undergone total abdominal hysterectomy with bilateral salpingo-oophorectomy or bilateral oophorectomy
  • The patient is medically confirmed to be menopausal (no menstrual period) for 24 consecutive month
  • Pre-pubertal females; the parent or guardian of young female patients who have not yet started menstruation should verify that menstruation has not begun; if a young female patient reaches menarche during the study, then she is to be considered as a woman of childbearing potential from that time forward
  • Ability to understand and the willingness to sign a written informed consent document
  • Patients with accessible tumor must agree to undergo pre- and post-treatment tumor biopsies

Who cannot join

  • Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 3 weeks earlier
  • Patients may not be receiving any other investigational agents
  • Patients with known brain metastases are excluded unless brain metastases have been resected or successfully treated with stereotactic radiosurgery and the patient has been free from central nervous system (CNS) recurrence or progression for 3 months
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to RO4929097 or other agents used in the study
  • Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible
  • Preclinical studies indicate that RO4929097 is a substrate of CYP3A4 and inducer of CYP3A4 enzyme activity; caution should be exercised when dosing RO4929097 concurrently with CYP3A4 substrates, inducers, and/or inhibitors; furthermore, patients who are taking concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4 should be switched to alternative medications to minimize any potential risk; the following medications with strong potential for interaction are not allowed: indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone
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  • Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption
  • Patients must be able to swallow tablets
  • Patients who are serologically positive for hepatitis A, B or C, and have an active infection, or have a history of liver disease, other forms of hepatitis or cirrhosis are ineligible
  • Patients with uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia or hypokalemia, defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation are excluded from this study
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, a history of torsades de pointes or other significant cardiac arrhythmias other than chronic, stable atrial fibrillation that require antiarrhythmics or other medications known to prolong corrected QT interval (QTc); psychiatric illness/social situations that would limit compliance with study requirements; patients may have had another cancer but there must be convincing clinical evidence that the melanoma is the disease requiring therapeutic intervention
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with RO4929097; these potential risks may also apply to other agents used in this study
  • HIV-positive patients on combination antiretroviral therapy are ineligible; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
  • Cardiovascular: baseline QTc > 450 msec (male) or QTc > 470 msec (female)
  • Patients who have not recovered to < Common Terminology Criteria for Adverse Events (CTCAE) grade 2 toxicities related to prior therapy are not eligible to participate in this study

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Memorial Sloan-Kettering Cancer Center

    New York, New York, 10065

Other trials in United States

About this study

Official title: Phase Ib/II Study of the Gamma-Secretase Inhibitor (GSI) RO4929097 in Combination With Cisplatin, Vinblastine, and Temozolomide (CVT) in Patients With Metastatic Melanoma

This phase Ib/II trial studies the side effects and best dose of gamma-secretase/Notch signalling pathway inhibitor RO4929097 when given together with cisplatin, vinblastine, and temozolomide and to see how well they work in treating patients with recurrent or metastatic melanoma. Gamma-secretase/Notch signalling pathway inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cisplatin, vinblastine, and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving gamma-secretase/Notch signalling pathway inhibitor RO4929097 together with combination chemotherapy may kill more tumor cells.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To characterize the safety and tolerability of daily RO4929097 (gamma-secretase/Notch signalling pathway inhibitor RO4929097) administered orally daily in combination with CVT (starting dose: cisplatin 25 mg/m^2 intravenous [IV] daily x 3; vinblastine 1.2 mg/m^2 IV daily x 3, and temozolomide [TMZ] 150 mg/m^2 orally [PO] daily x 5) administered on an every 21 day schedule. (Phase Ib) II. To determine the maximum-tolerated dose (MTD) of RO4929097 with CVT in patients with metastatic melanoma with correlative biomarkers for Notch pathway signaling and gamma secretase enzyme activity. (Phase Ib) III. Based on the MTD from the phase Ib study, to conduct a phase II trial and to determine the response rate and overall survival. (Phase II)

SECONDARY OBJECTIVES:

  1. To describe the pharmacokinetics and pharmacodynamics of the combination of RO4929097 and temozolomide. (Phase Ib) II. To obtain tissue biopsy for correlative studies before the initiation of therapy and one week after treatment with RO4929097 and CVT. (Phase Ib and II) III. To determine the progression-free survival of patients treated at the phase II dose. (Phase II)

OUTLINE: This is phase I dose-escalation study of gamma-secretase inhibitor RO4929097, followed by a phase II study.

Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO once daily (QD) on days 1-21, cisplatin IV over 30 minutes and vinblastine IV over 30 minutes on days 1-3, and temozolomide PO QD on days 1-5. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients without progressive disease continue to receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 and temozolomide as above in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up for 24 months.

Being tested
Cisplatin, Gamma-Secretase Inhibitor RO4929097, Laboratory Biomarker Analysis, Pharmacological Study, Temozolomide
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CisplatinDrug

    Also called Abiplatin, Blastolem, Briplatin, CDDP

    Given IV

  • Gamma-Secretase Inhibitor RO4929097Drug

    Also called RO4929097

    Given PO

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • Pharmacological StudyOther

    Correlative studies

  • TemozolomideDrug

    Also called CCRG-81045, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831, M and B 39831

    Given PO

  • Vinblastine SulfateDrug

    Also called 29060 LE, 29060-LE, Exal, Velban

    Given IV

Study groups in NCT01196416
Study groupRoleWhat they receive
Treatment (RO4929097, cisplatin, vinblastine, temozolomide)ExperimentalPatients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days 1-21, cisplatin IV over 30 minutes and vinblastine IV over 30 minutes on days 1-3, and temozolomide PO QD on days 1-5. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients without progressive disease continue to receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 and temozolomide as above in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Cisplatin; Drug: Gamma-Secretase Inhibitor RO4929097; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Temozolomide; Drug: Vinblastine Sulfate

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Overall Objective Response

    Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression

    Measured: From the time measurement criteria are met for CR or PR until the first date that recurrent or progressive disease is objectively documented, assessed up to 2 years

  2. Maximum-tolerated Dose for Cisplatin, Vinblastine and TMZ

    based on the incidence of dose-limiting toxicity as assessed the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase IB)

    Data is not yet available, as it's currently being analyzed.

    Measured: 21 days

  3. Overall Survival (Phase II)

    Overall response rate (complete [CR] or partial response [PR]) according to RECIST version 1.1

    Measured: Up to 2 years

  4. Maximum Tolerated Dose for RO4929097

    based on the incidence of dose-limiting toxicity as assessed the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase IB)

    Measured: 21 days

Secondary outcomes (7)

  1. Participants' Change in Protein Levels

    Participants' pre and post-treatment protein levels will be compared

    Measured: Baseline up to 2 weeks

  2. Cycle 1 AUC/Pharmacokinetics of Gamma-secretase Inhibitor RO4929097 in Combination With Temozolomide (Phase IB)

    Measured: Days 4 and 5

  3. Cycle 1 C Max/Pharmacokinetics of Gamma-secretase Inhibitor RO4929097 in Combination With Temozolomide (Phase IB)

    Measured: At Cycle 1

  4. Cycle 1 Mean Day 2 Trough/Pharmacokinetics of Gamma-secretase Inhibitor RO4929097 in Combination With Temozolomide (Phase IB)

    Measured: At Day 2 of Cycle 1

  5. Number of Participants With Presence or Absence of Markers of Notch Signalling Pathway Inhibition in Patient Tumors (Phase Ib)

    The association of response or clinical benefit with the presence or absence of markers of pathway inhibition in patient tumors will be tested using Fisher's exact test.

    Measured: 2 weeks

  6. Progression-free Survival (Phase II)

    Progression-free survival curves will be generated using Kaplan-Meier methodology.

    Measured: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years

  7. Participants Evaluated for Toxicity

    Number of patients with AE's as assessed by NCI CTCAE v. 4.0 Please see Adverse Events section for specifics.

    Measured: Up to 30 days post-treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Sep 2010 (estimated)
  2. Study startAug 2010
  3. Primary completionAug 2015
  4. Study completionAug 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
14 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01196416
Sponsor's protocol ID
NCI-2011-02524
Other IDs
NCI-2011-02524, CDR0000684220, 10-085, 8491, N01CM62206, P30CA008748, U01CA069856
Status last verified
Oct 2019
First submitted
4 Sep 2010
Last updated
18 Nov 2019

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Cisplatin, Gamma-Secretase Inhibitor RO4929097 and Laboratory Biomarker Analysis in people with Recurrent Melanoma and Stage IV Skin Melanoma, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 24 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 Nov 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 18 Oct 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall Objective Response (time frame: From the time measurement criteria are met for CR or PR until the first date that recurrent or progressive disease is objectively documented, assessed up to 2 years). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01196416.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Nov 2019.

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